Neuroscience

Some breast tumor circulating cells in the bloodstream are marked by a constellation of biomarkers that identify them as those destined to seed the brain with a deadly spread of cancer, said researchers led by those at Baylor College of Medicine in a report that appears online in the journal Science Translational Medicine.

"What prompted us to initiate this study was our desire to understand the characteristics of these cells," said Dr. Dario Marchetti, professor of pathology at BCM, director of the CTC (circulating tumor cell) Core Facility at BCM and a member of the NCI-designated Dan L. Duncan Cancer Center at BCM. Often, he said, circulating tumor cells (CTCs) from breast cancer patients which spread or metastasize to the brain are not identified by the current method for identifying such cells approved by the U.S. Food and Drug Administration (CellSearch® platform).

While this system is based on the detection of antibodies that target the epithelial cell adhesion molecule (EpCAM), the biomarkers identified by Marchetti and his colleagues include human epidermal growth factor receptor 2 (HER2+), epidermal growth factor receptor (EGFR), heparanase (HPSE) and Notch1 - and not EpCAM. Together, said Marchetti, these four proteins, previously known to be associated with cancer metastasis, spell out the signature of circulating tumors cells that travel to the brain.

Marchetti, using sophisticated techniques to test samples provided by Dr. Morris D. Groves of The University of Texas MD Anderson Cancer Center, also found this same pattern of proteins in the tissue taken from brain metastases of animals injected with breast cancer circulating tumor cells (CTCs).

They tested these special circulating tumor cells in laboratory models and found that they are highly invasive and capable of spread in live animals. They also found cells with this signature in the metastatic tumors of animals with breast cancer.

"We were able to grow these cells in vitro (in the laboratory in culture) for the first time ever," said Marchetti.

Circulating tumor cells are a promising method of identifying and monitoring solid tumors and could replace tumor biopsies in some cases. However, the promise is still being studied by experts such as Marchetti. In this case, he has identified a new signature for such cells - one that directs their activities toward spreading cancer to brain - an outcome with frequently fatal consequences.

The study not only identifies a novel signature of circulating tumor cells, it shows the limitations of currently approved platforms used to identify cancer in this way. Understanding such cells can help scientist understand how the disease spreads - an initial step in developing new methods of treating metastatic disease.

"We don’t claim that these biomarkers are the only important ones," said Marchetti. "We hope to find novel markers in brain metastasis that will make diagnosis and monitoring even more targeted."

They are also trying to find ways to link these circulating tumor cells back to the signature of the original or primary tumor.

Tapeworm infection in the brain that can trigger seizures is a growing health concern, doctors say.

But the infection, which leads to swelling in the brain, is usually treatable with medication, according to a leading association of neurologists.

Estimated cases of neurocysticercosis, as the tapeworm infection is called, range from 40,000 to 160,000 each year in the United States, said Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston. “It’s been around a long time, affecting people living in severe poverty, but the disease is not well-studied or understood,” Hotez said.

Texas is one area of the country with many cases. “The disease has now become a leading cause of epilepsy in Houston,” Hotez said. “Every [week], we have patients come into our tropical medicine clinic with it.”

Concerns about an apparent increase of neurocysticercosis within the United States led the American Academy of Neurology to issue treatment guidelines for doctors and patients in the April 9 issue of the journal Neurology.

The recommendations are based on a review of 10 studies published between 1980 and 2010 that evaluated so-called cysticidal drugs for treatment of tapeworm infections. The infection involves infestation of the brain with the larvae of the Taenia solium tapeworm. In severe cases, it can cause death.

Tapeworm infection is common in Third World countries because of inadequate sanitation and hygiene, and an estimated 2 million people worldwide have epilepsy as a result. The good news is that good hygiene and food preparation can prevent it.

People develop the tapeworm infection when they consume improperly cooked meat, such as pork, or any food or drink that contains the tapeworm eggs or larvae (also known as cysts). Touching the fecal matter of an infected person is another means of transmission. The larvae then transform into full-sized tapeworms, which can grow to several feet, Hotez said.

In pigs, tapeworm larvae travel to the brain and await transmission to another animal (a human, for instance) when the pigs are eaten, he said. The parasites do the same thing in humans, but there’s nowhere to go from the human brain. Ultimately, the larvae die, and that’s when the trouble begins.

As the larvae die, they lose the ability to hide from the body’s immune system. The immune system responds by causing inflammation, which leads to epileptic seizures and brain swelling, Hotez said.

The guidelines for children and adults recommend using the medication albendazole to kill the cysts if they’re alive and treating brain swelling with corticosteroid drugs that dampen the immune system. The study found that albendazole (Albenza), used with or without the corticosteroids, reduced seizure frequency and the number of brain lesions seen in imaging scans. Not enough data was available to evaluate another drug, praziquantel, the researchers said.

Only limited evidence exists to support specific treatment approaches, however, and the treatments may produce side effects, such as abdominal complaints, according to the guidelines. It’s also unclear whether anti-epileptic medications may help prevent the seizures caused by the inflammation.

For now, the key is physician awareness, said Dr. Karen Roos, a professor of neurology at the Indiana University School of Medicine and lead author of the guidelines. “Physicians from areas of the world where this infection is endemic are very knowledgeable about this infection,” she said. “They know more than U.S. physicians.”

Infection with the tapeworm is preventable through proper sanitation, good hygiene and thorough cooking of meat.

Obesity, heart disease, and high blood pressure (hypertension) are all related, but understanding the molecular pathways that underlie cause and effect is complicated.

A new University of Iowa study identifies a protein within certain brain cells as a communications hub for controlling blood pressure, and suggests that abnormal activation of this protein may be a mechanism that links cardiovascular disease and obesity to elevated blood pressure.

"Cardiovascular diseases are the leading cause of death worldwide, and hypertension is a major cardiovascular risk factor," says Kamal Rahmouni, UI associate professor of pharmacology and internal medicine, and senior study author. "Our study identifies the protein called mTORC1 in the hypothalamus as a key player in the control of blood pressure. Targeting mTORC1 pathways may, therefore, be a promising strategy for the management of cardiovascular risk factors."

The hypothalamus is a small region of the brain that is responsible for maintaining normal function for numerous bodily processes, including blood pressure, body temperature, and glucose levels. Signaling of mTORC1 protein in the hypothalamus has previously been shown to affect food intake and body weight.

The new study, which was published April 2 in the journal Cell Metabolism, shows that the mTORC1 protein is activated by small molecules and hormones that are associated with obesity and cardiovascular disease, and this activation leads to dramatic increases in blood pressure.

Leucine is an amino acid that we get from food, which is known to activate mTORC1. The UI researchers showed that activating mTORC1 in rat brains with leucine increased activity in the nerves that connect the brain to the kidney, an important organ in blood pressure control. The increased nerve activity was accompanied by a rise in blood pressure. Conversely, blocking this mTORC1 activation significantly blunted leucine’s blood pressure-raising effect.

This finding may have direct clinical relevance as elevated levels of leucine have been correlated with an increased risk of high blood pressure in patients with cardiovascular disease.

"Our new study suggests a mechanism by which leucine in the bloodstream might increase blood pressure,” Rahmouni says.

Previous work has also suggested that mTORC1 is a signaling hub for leptin, a hormone produced by fat cells, which has been implicated in obesity-related hypertension.

Rahmouni and his colleagues showed that leptin activates mTORC1 in a specific part of the hypothalamus causing increased nerve activity and a rise in blood pressure. These effects are blocked by inhibiting activation of mTORC1.

“Our study shows that when this protein is either activated or inhibited in a very specific manner, it can cause dramatic changes in blood pressure,” Rahmouni says. “Given the importance of this protein for the control of blood pressure, any abnormality in its activity might explain the hypertension associated with certain conditions like obesity and cardiovascular disease.”

Rahmouni and his team hope that uncovering the details of the pathways linking mTORC1 activation and high blood pressure might lead to better treatments for high blood pressure in patients with cardiovascular disease and obesity.

New research has questioned the reliability of neuroscience studies, saying that conclusions could be misleading due to small sample sizes.

A team led by academics from the University of Bristol reviewed 48 articles on neuroscience meta-analysis which were published in 2011 and concluded that most had an average power of around 20 per cent – a finding which means the chance of the average study discovering the effect being investigated is only one in five.

The paper, being published in Nature Reviews Neuroscience, reveals that small, low-powered studies are ‘endemic’ in neuroscience, producing unreliable research which is inefficient and wasteful.

It focuses on how low statistical power – caused by low sample size of studies, small effects being investigated, or both – can be misleading and produce more false scientific claims than high-powered studies.

It also illustrates how low power reduces a study’s ability to detect any effects and shows that when discoveries are claimed, they are more likely to be false or misleading.

The paper claims there is substantial evidence that a large proportion of research published in scientific literature may be unreliable as a consequence.

Another consequence is that the findings are overestimated because smaller studies consistently give more positive results than larger studies. This was found to be the case for studies using a diverse range of methods, including brain imaging, genetics and animal studies.

Kate Button, from the School of Social and Community Medicine, and Marcus Munafò, from the School of Experimental Psychology, led a team of researchers from Stanford University, the University of Virginia and the University of Oxford.

She said: “There’s a lot of interest at the moment in improving the reliability of science. We looked at neuroscience literature and found that, on average, studies had only around a 20 per cent chance of detecting the effects they were investigating, even if the effects are real. This has two important implications - many studies lack the ability to give definitive answers to the questions they are testing, and many claimed findings are likely to be incorrect or unreliable.”

The study concludes that improving the standard of results in neuroscience, and enabling them to be more easily reproduced, is a key priority and requires attention to well-established methodological principles.

It recommends that existing scientific practices can be improved with small changes or additions to methodologies, such as acknowledging any limitations in the interpretation of results; disclosing methods and findings transparently; and working collaboratively to increase the total sample size and power.

The eyes sometimes have it, beating out the tongue, nose and brain in the emotional and biochemical balloting that determines the taste and allure of food, a scientist said here today. Speaking at the 245^th National Meeting & Exposition of the American Chemical Society (ACS), the world’s largest scientific society, he described how people sometimes “see” flavors in foods and beverages before actually tasting them.

“There have been important new insights into how people perceive food flavors,” said Terry E. Acree, Ph.D. “Years ago, taste was a table with two legs — taste and odor. Now we are beginning to understand that flavor depends on parts of the brain that involve taste, odor, touch and vision. The sum total of these signals, plus our emotions and past experiences, result in perception of flavors, and determine whether we like or dislike specific foods.”

Acree said that people actually can see the flavor of foods, and the eyes have such a powerful role that they can trump the tongue and the nose. The popular Sauvignon Blanc white wine, for instance, gets its flavor from scores of natural chemicals, including chemicals with the flavor of banana, passion fruit, bell pepper and boxwood. But when served a glass of Sauvignon Blanc tinted to the deep red of merlot or cabernet, people taste the natural chemicals that give rise to the flavors of those wines.

The sense of smell likewise can trump the taste buds in determining how things taste, said Acree, who is with Cornell University. In a test that people can do at home, psychologists have asked volunteers to smell caramel, strawberry or other sweet foods and then take a sip of plain water; the water will taste sweet. But smell bread, meat, fish or other non-sweet foods, and water will not taste sweet.

While the appearance of foods probably is important, other factors can override it. Acree pointed out that hashes, chilies, stews and cooked sausages have an unpleasant look, like vomit or feces. However, people savor these dishes based on the memory of eating and enjoying them in the past. The human desire for novelty and new experiences also is a factor in the human tendency to ignore what the eyes may be tasting and listening to the tongue and nose, he added.

Acree said understanding the effects of interactions between smell and vision and taste, as well as other odorants, will open the door to developing healthful foods that look and smell more appealing to finicky kids or adults.

Why do some memories last a lifetime while others disappear quickly?

(Image: Tim Vernon, LTH NHS TRUST/SCIENCE PHOTO LIBRARY)

A new study suggests that memories rehearsed, during either sleep or waking, can have an impact on memory consolidation and on what is remembered later.

The new Northwestern University study shows that when the information that makes up a memory has a high value (associated with, for example, making more money), the memory is more likely to be rehearsed and consolidated during sleep and, thus, be remembered later.

Also, through the use of a direct manipulation of sleep, the research demonstrated a way to encourage the reactivation of low-value memories so they too were remembered later.

Delphine Oudiette, a postdoctoral fellow in the department of psychology at Northwestern and lead author of the study, designed the experiment to study how participants remembered locations of objects on a computer screen. A value assigned to each object informed participants how much money they could make if they remembered it later on the test.

"The pay-off was much higher for some of the objects than for others," explained Ken Paller, professor of psychology at Northwestern and co-author of the study. "In other words, we manipulated the value of the memories — some were valuable memories and others not so much, just as the things we experience each day vary in the extent to which we’d like to be able to remember them later."

When each object was shown, it was accompanied by a characteristic sound. For example, a tea kettle would appear with a whistling sound. During both states of wakefulness and sleep, some of the sounds were played alone, quite softly, essentially reminding participants of the low-value items.

Participants remembered the low-value associations better when the sound presentations occurred during sleep.

"We think that what’s happening during sleep is basically the reactivation of that information," Oudiette said. "We can provoke the reactivation by presenting those sounds, therefore energizing the low-value memories so they get stored better."

The research poses provocative implications about the role memory reactivation during sleep could play in improving memory storage,” said Paller, director of the Cognitive Neuroscience Program at Northwestern. “Whatever makes you rehearse during sleep is going to determine what you remember later, and conversely, what you’re going to forget.”

Many memories that are stored during the day are not remembered.

"We think one of the reasons for that is that we have to rehearse memories in order to keep them. When you practice and rehearse, you increase the likelihood of later remembering," Oudiette said. "And a lot of our rehearsal happens when we don’t even realize it — while we’re asleep."

Paller said selectivity of memory consolidation is not well understood. Most efforts in memory research have focused on what happens when you first form a memory and on what happens when you retrieve a memory.

"The in-between time is what we want to learn more about, because a fascinating aspect of memory storage is that it is not static," Paller said. "Memories in our brain are changing all of the time. Sometimes you improve memory storage by rehearsing all the details, so maybe later you remember better — or maybe worse if you’ve embellished too much.

"The fact that this critical memory reactivation transpires during sleep has mostly been hidden from us, from humanity, because we don’t realize so much of what’s happening while we’re asleep," he said.

Protein spheres in the nucleus give wrong signal for cell division

RUB researchers develop new hypothesis for the degeneration of nerve cells

A new hypothesis has been developed by researchers in Bochum on how Alzheimer’s disease could occur. They analysed the interaction of the proteins FE65 and BLM that regulate cell division. In the cell culture model, they discovered spherical structures in the nucleus that contained FE65 and BLM. The interaction of the proteins triggered a wrong signal for cell division. This may explain the degeneration and death of nerve cells in Alzheimer’s patients. The team led by Dr. Thorsten Müller and Prof. Dr. Katrin Marcus from the Department of Functional Proteomics in cooperation with the RUB’s Medical Proteome Centre headed by Prof. Helmut E. Meyer reported on the results in the “Journal of Cell Science”.

Components of spherical structures in the nucleus identified

The so-called amyloid precursor protein APP is central to Alzheimer’s disease. It spans the cell membrane, and its cleavage products are linked to protein deposits that form in Alzheimer patients outside the nerve cells. APP anchors the protein FE65 to the membrane, which was the focus of the current study. FE65 can migrate into the nucleus, where it plays a role in DNA replication and repair. Based on cells grown in the laboratory, the team led by Dr. Müller established that FE65 can unite with other proteins in the cell nucleus to form spherical structures, so-called “nuclear spheres”. Video microscopy showed that these ring-like structures merge with each other and can thus grow. “By using a special cell culture model, we were able to identify additional components of these spheres”, says Andreas Schrötter, PhD student in the working group Morbus Alzheimer at the Institute for Functional Proteomics. Among other things, the scientists found the protein BLM, which is known from Bloom’s syndrome – an extremely rare hereditary disease, which is associated with dwarfism, immunodeficiency, and an increased risk of cancer. BLM is involved in DNA replication and repair in the nucleus.

The amount of FE65 determines the amount of BLM in the cell nucleus

Müller’s team took a closer look at the function of FE65. By means of genetic manipulation, the researchers generated cell cultures, in which the FE65-production was reduced. A smaller amount of FE65 thus generated a smaller amount of the protein BLM in the nucleus. Instead, BLM collected in another area of the cell, the endoplasmic reticulum. In addition, the researchers found a lower rate of DNA replication in the genetically modified cells. In this way, FE65 influences the replication of the genetic material via the BLM protein. When the researchers cranked up the FE65-production again, the amount of BLM in the nucleus also increased again.

FE65 as a possible trigger for Alzheimer’s

In patients with Alzheimer’s disease, the protein APP, an interaction partner of FE65, changes. The interaction of the two molecules is important for the transport of FE65 into the nucleus, where it regulates cell division in combination with BLM. Müller’s team assumes that the altered APP-FE65 interaction mistakenly sends the cells the signal to divide. Since nerve cells normally cannot divide, they degenerate instead and die. “This hypothesis, which we pursue in the working group Morbus Alzheimer, also delivers new starting points for potential therapies, which are urgently needed for Alzheimer’s disease,” says Dr. Mueller. In the future, the team will also investigate whether and how the amount of BLM is altered in Alzheimer’s patients compared to healthy subjects.

We’ve all been there: You’re at work deeply immersed in a project when suddenly you start thinking about your weekend plans. It happens because behind the scenes, parts of your brain are battling for control.

Now, University of Florida researchers and their colleagues are using a new technique that allows them to examine how parts of the brain battle for dominance when a person tries to concentrate on a task. Addressing these fluctuations in attention may help scientists better understand many neurological disorders such as autism, depression and mild cognitive impairment.

Mingzhou Ding, a professor of biomedical engineering, and Xiaotong Wen, an assistant research scientist of biomedical engineering, both of the University of Florida; Yijun Liu of the McKnight Brain Institute of the University of Florida and Peking University, Beijing; and Li Yao of Beijing Normal University, report their findings in the current issue of The Journal of Neuroscience.

Scientists know different networks within the brain have distinct functions. Ding, Wen and their colleagues used a brain imaging technique called functional magnetic resonance imaging and biostatistical methods to examine interactions between a set of areas they call the task control network and another set of areas known as the default mode network.

The task control network regulates attention to surroundings, controlling concentration on a task such as doing homework, or listening for emotional cues during a conversation. The default mode network is thought to regulate self-reflection and emotion, and often becomes active when a person seems to be doing nothing else.

“We knew that the default mode network decreases in activity when a task is being performed, but we didn’t know why or how,” said Ding, a professor of biomedical engineering in the J. Crayton Pruitt department of biomedical engineering. “We also wanted to know what is driving that activity decrease.

“For a long time, the questions we are asking could not be answered.”

In the past, researchers could not distinguish between directions of interactions between regions of the brain, and could come up with only one number to represent an average of the back-and-forth interactions. Ding and his colleagues used a new technique to untangle the interactions in each direction to show how the different brain regions interact with one another.

In their study, the researchers used fMRI to examine the brains of people performing a task that required concentration. The scientists can see the activity in certain areas of the brain at the same time a person is performing a given task. They can see which parts of the brain are active and which are not and correlate this to how successful a person is at a given task. They then applied the Granger causality technique to look at the data they saw in the fMRI. Named for Nobel Prize-winning economist Clive Granger, this technique allows scientists to examine how one variable affects another variable; in this case, how one region of the brain influences another.

“People have hypothesized different functions for signals going in different directions,” Ding said. “We show that when the task control network suppresses the default mode network, the person can do the task better and faster. The better the default mode network is shut down, the better a person performs.”

However, when the default mode network is not sufficiently suppressed, it sends signals to the task control network that effectively distract the person, causing his or her performance to drop. So while the task control network suppresses the default mode network, the default mode network also interferes with the task control network.

“Your brain is a constant seesaw back and forth,” even when trying to concentrate on a task, Ding said.

The Granger causality technique may help researchers learn more about how neurological disorders work. Researchers have found that the default mode network remains unchanged in people with autism whether they are performing a task or interacting with the environment, which could explain symptoms such as difficulty reading social cues or being easily overwhelmed by sensory stimulation. Scientists have made similar findings with depression and mild cognitive impairment. However, until now no one has been able to address what areas of the brain might be regulating the default mode network and which might be interfering with that regulation.

“Now we are able to address these questions,” Ding said.

Using a miniature electronic device implanted in the brain, scientists have tapped into the internal reward system of mice, prodding neurons to release dopamine, a chemical associated with pleasure.

The researchers, at Washington University School of Medicine in St. Louis and the University of Illinois at Urbana-Champaign, developed tiny devices, containing light emitting diodes (LEDs) the size of individual neurons. The devices activate brain cells with light. The scientists report their findings April 12 in the journal Science.

“This strategy should allow us to identify and map brain circuits involved in complex behaviors related to sleep, depression, addiction and anxiety,” says co-principal investigator Michael R. Bruchas, PhD, assistant professor of anesthesiology at Washington University. “Understanding which populations of neurons are involved in these complex behaviors may allow us to target specific brain cells that malfunction in depression, pain, addiction and other disorders.”

For the study, Washington University neuroscientists teamed with engineers at the University of Illinois to design microscale (LED) devices thinner than a human hair. This was the first application of the devices in optogenetics, an area of neuroscience that uses light to stimulate targeted pathways in the brain. The scientists implanted them into the brains of mice that had been genetically engineered so that some of their brain cells could be activated and controlled with light.

Although a number of important pathways in the brain can be studied with optogenetics, many neuroscientists have struggled with the engineering challenge of delivering light to precise locations deep in the brain. Most methods have tethered animals to lasers with fiber optic cables, limiting their movement and altering natural behaviors.

But with the new devices, the mice freely moved about and were able to explore a maze or scamper on a wheel. The electronic LEDs are housed in a tiny fiber implanted deep in the brain. That’s important to the device’s ability to activate the proper neurons, according to John A. Rogers, PhD, professor of materials science and engineering at the University of Illinois.

“You want to be able to deliver the light down into the depth of the brain,” Rogers says. “We think we’ve come up with some powerful strategies that involve ultra-miniaturized devices that can deliver light signals deep into the brain and into other organs in the future.”

Using light from the cellular-scale LEDs to stimulate dopamine-producing cells in the brain, the investigators taught the mice to poke their noses through a specific hole in a maze. Each time a mouse would poke its nose through the hole, that would trigger the system to wirelessly activate the LEDs in the implanted device, which then would emit light, causing neurons to release dopamine, a chemical related to the brain’s natural reward system.

“We used the LED devices to activate networks of brain cells that are influenced by the things you would find rewarding in life, like sex or chocolate,” says co-first author Jordan G. McCall, a neuroscience graduate student in Washington University’s Division of Biology and Biomedical Sciences. “When the brain cells were activated to release dopamine, the mice quickly learned to poke their noses through the hole even though they didn’t receive any food as a reward. They also developed an associated preference for the area near the hole, and they tended to hang around that part of the maze.”

The researchers believe the LED implants may be useful in other types of neuroscience studies or may even be applied to different organs. Related devices already are being used to stimulate peripheral nerves for pain management. Other devices with LEDs of multiple colors may be able to activate and control several neural circuits at once. In addition to the tiny LEDs, the devices also carry miniaturized sensors for detecting temperature and electrical activity within the brain.

Bruchas and his colleagues already have begun other studies of mice, using the LED devices to manipulate neural circuits that are involved in social behaviors. This could help scientists better understand what goes on in the brain in disorders such as depression and anxiety.

“We believe these devices will allow us to study complex stress and social interaction behaviors,” Bruchas explains. “This technology enables us to map neural circuits with respect to things like stress and pain much more effectively.”

The wireless, microLED implant devices represent the combined efforts of Bruchas and Rogers. Last year, along with Robert W. Gereau IV, PhD, professor of anesthesiology, they were awarded an NIH Director’s Transformative Research Project award to develop and conduct studies using novel device development and optogenetics, which involves activating or inhibiting brain cells with light.

Scientists at The Scripps Research Institute (TSRI) have shed light on one of the major toxic mechanisms of Alzheimer’s disease. The discoveries could lead to a much better understanding of the Alzheimer’s process and how to prevent it.

The findings, reported in the April 10, 2013 issue of the journal Neuron, show that brain damage in Alzheimer’s disease is linked to the overactivation of an enzyme called AMPK. When the scientists blocked this enzyme in mouse models of the disease, neurons were protected from loss of synapses—neuron-to-neuron connection points—typical of the early phase of Alzheimer’s disease.

“These findings open up many new avenues of investigation, including the possibility of developing therapies that target the upstream mechanisms leading to AMPK overactivation in the brain,” said TSRI Professor Franck Polleux, who led the new study.

Alzheimer’s disease, a fatal neurodegenerative disorder afflicting more than 25 million people worldwide, currently has no cure or even disease-delaying therapy.

In addition to having implications for Alzheimer’s drug discovery, Polleux noted the findings suggest the need for further safety studies on an existing drug, metformin. Metformin, apopular treatment for Type 2 Diabetes, causes AMPK activation.

Tantalizing Clues to Alzheimer’s

Researchers have known for years that people in the earliest stages of Alzheimer’s disease begin to lose synapses in certain memory-related brain areas. Small aggregates of the protein amyloid beta can cause this loss of synapses, but how they do so has been a mystery.

Until recently, Polleux’s laboratory has been focused not on Alzheimer’s research but on the normal development and growth of neurons. In 2011, he and his colleagues reported that AMPK overactivation by metformin, among other compounds, in animal models impaired the ability of neurons to grow output stalks, or axons.

Around the same time, separate research groups found clues that AMPK might also have a role in Alzheimer’s disease. One group reported that AMPK can be activated in neurons by amyloid beta, which in turn can cause a modification of the protein tau in a process known as phosphorylation. Tangles of tau with multiple phosphorylations (“hyperphosphorylated” tau) are known to accumulate in neurons in affected brain areas in Alzheimer’s. These results, published two years ago, reported abnormally high levels of activated AMPK in these tangle-ridden neurons.

Polleux decided to investigate further, to determine whether the reported interactions of AMPK with amyloid beta and tau can in fact cause the damage seen in the brains of Alzheimer’s patients. “Very little was known about the function of this AMPK pathway in neurons, and we happened to have all the tools needed to study it,” he said.

In Search of Answers

Georges Mairet-Coello, a postdoctoral research associate in the Polleux lab, performed most of the experiments for the new study. He began by confirming that amyloid beta, in the small-aggregate (“oligomer”) form that is toxic to synapses, does indeed strongly activate AMPK; amyloid beta oligomers stimulate certain neuronal receptors, which in turn causes an influx of calcium ions into the neurons. He found that this calcium influx triggers the activation of an enzyme called CAMKK2, which appears to be the main activator of AMPK in neurons.

The team then showed that this AMPK overactivation in neurons is the essential reason for amyloid beta’s synapse-harming effect. Normally, the addition of amyloid beta oligomers to a culture of neurons causes the swift disappearance of many of the neurons’ dendritic spines—the rootlike, synapse-bearing input stalks that receive signals from other neurons. With a variety of tests, the scientists showed that amyloid beta oligomers can’t cause this dendritic spine loss unless AMPK overactivation occurs—and indeed AMPK overactivation on its own can cause the spine loss.

For a key experiment the team used J20 mice, which are genetically engineered to overproduce mutant amyloid beta, and eventually develop an Alzheimer’s-like condition. “When J20 mice are only three months old, they already show a strong decrease in dendritic spine density, in a set of memory-related neurons that are also affected early in human Alzheimer’s,” Mairet-Coello said. “But when we blocked the activity of CAMKK2 or AMPK in these neurons, we completely prevented the spine loss.”

Next Mairet-Coello investigated the role of the tau protein. Ordinarily it serves as a structural element in neuronal axons, but in Alzheimer’s it somehow becomes hyperphosphorylated and drifts into other neuronal areas, including dendrites where its presence is associated with spine loss. Recent studies have shown that amyloid beta’s toxicity to dendritic spines depends largely on the presence of tau, but just how the two Alzheimer’s proteins interact has been unclear.

The team took a cue from a 2004 study of Drosophila fruit flies, in which an AMPK-like enzyme’s phosphorylation of specific sites on the tau protein led to a cascade of further phosphorylations and the degeneration of nerve cells. The scientists confirmed that one of these sites, S262, is indeed phosphorylated by AMPK. They then showed that this specific phosphorylation of tau accounts to a significant extent for amyloid beta’s synapse toxicity. “Blocking the phosphorylation at S262, by using a mutant form of tau that can’t be phosphorylated at that site, prevented amyloid beta’s toxic effect on spine density,” Mairet-Coello said.

The result suggests that amyloid beta contributes to Alzheimer’s via AMPK, mostly as an enabler of tau’s toxicity.

More Studies Ahead

Mairet-Coello, Polleux and their colleagues are now following up with further experiments to determine what other toxic processes, such as excessive autophagy, are promoted by AMPK overactivation and might also contribute to the long-term aspects of Alzheimer’s disease progression. They are also interested in the long-term effects of blocking AMPK overactivation in the J20 mouse model as well as in other mouse models of Alzheimer’s disease, which normally develop cognitive deficits at later stages. “We already have contacts within the pharmaceuticals industry who are potentially interested in targeting either CAMKK2 or AMPK,” says Polleux.

The other contributors to the study, “The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of amyloid beta oligomers through tau phosphorylation,” were Julien Courchet, Simon Pieraut, Virginie Courchet and Anton Maximov, all of TSRI.

Do the brains of different people listening to the same piece of music actually respond in the same way? An imaging study by Stanford University School of Medicine scientists says the answer is yes, which may in part explain why music plays such a big role in our social existence.

(Image: Anthony Ellis)

The investigators used functional magnetic resonance imaging to identify a distributed network of several brain structures whose activity levels waxed and waned in a strikingly similar pattern among study participants as they listened to classical music they’d never heard before. The results will be published online April 11 in the European Journal of Neuroscience.

"We spend a lot of time listening to music — often in groups, and often in conjunction with synchronized movement and dance," said Vinod Menon, PhD, a professor of psychiatry and behavioral sciences and the study’s senior author. "Here, we’ve shown for the first time that despite our individual differences in musical experiences and preferences, classical music elicits a highly consistent pattern of activity across individuals in several brain structures including those involved in movement planning, memory and attention."

The notion that healthy subjects respond to complex sounds in the same way, Menon said, could provide novel insights into how individuals with language and speech disorders might listen to and track information differently from the rest of us.

The new study is one in a series of collaborations between Menon and co-author Daniel Levitin, PhD, a psychology professor at McGill University in Montreal, dating back to when Levitin was a visiting scholar at Stanford several years ago.

To make sure it was music, not language, that study participants’ brains would be processing, Menon’s group used music that had no lyrics. Also excluded was anything participants had heard before, in order to eliminate the confounding effects of having some participants who had heard the musical selection before while others were hearing it for the first time. Using obscure pieces of music also avoided tripping off memories such as where participants were the first time they heard the selection.

The researchers settled on complete classical symphonic musical pieces by 18th-century English composer William Boyce, known to musical cognoscenti as “the English Bach” because his late-baroque compositions in some respects resembled those of the famed German composer. Boyce’s works fit well into the canon of Western music but are little known to modern Americans.

Next, Menon’s group recruited 17 right-handed participants (nine men and eight women) between the ages of 19 and 27 with little or no musical training and no previous knowledge of Boyce’s works. (Conventional maps of brain anatomy are based on studies of right-handed people. Left-handed people’s brains tend to deviate from that map.)

While participants listened to Boyce’s music through headphones with their heads maintained in a fixed position inside an fMRI chamber, their brains were imaged for more than nine minutes. During this imaging session, participants also heard two types of “pseudo-musical” stimuli containing one or another attribute of music but lacking in others. In one case, all of the timing information in the music was obliterated, including the rhythm, with an effect akin to a harmonized hissing sound. The other pseudo-musical input involved maintaining the same rhythmic structure as in the Boyce piece but with each tone transformed by a mathematical algorithm to another tone so that the melodic and harmonic aspects were drastically altered.

The team identified a hierarchal network stretching from low-level auditory relay stations in the midbrain to high-level cortical brain structures related to working memory and attention, and beyond that to movement-planning areas in the cortex. These regions track structural elements of a musical stimulus over time periods lasting up to several seconds, with each region processing information according to its own time scale.

Activity levels in several different places in the brain responded similarly from one individual to the next to music, but less so or not at all to pseudo-music. While these brain structures have been implicated individually in musical processing, their identifications had been obtained by probing with artificial laboratory stimuli, not real music. Nor had their coordination with one another been previously observed.

Notably, subcortical auditory structures in the midbrain and thalamus showed significantly greater synchronization in response to musical stimuli. These structures have been thought to passively relay auditory information to higher brain centers, Menon said. “But if they were just passive relay stations, their responses to both types of pseudo-music would have been just as closely synchronized between individuals as to real music.” The study demonstrated, for the first time, that those structures’ activity levels respond preferentially to music rather than to pseudo-music, suggesting that higher-level centers in the cortex direct these relay stations to closely heed sounds that are specifically musical in nature.

The fronto-parietal cortex, which anchors high-level cognitive functions including attention and working memory, also manifested intersubject synchronization — but only in response to music and only in the right hemisphere.

Interestingly, the structures involved included the right-brain counterparts of two important structures in the brain’s left hemisphere, Broca’s and Geschwind’s areas, known to be crucial for speech and language interpretation.

"These right-hemisphere brain areas track non-linguistic stimuli such as music in the same way that the left hemisphere tracks linguistic sequences," said Menon.

In any single individual listening to music, each cluster of music-responsive areas appeared to be tracking music on its own time scale. For example, midbrain auditory processing centers worked more or less in real time, while the right-brain analogs of the Broca’s and Geschwind’s areas appeared to chew on longer stretches of music. These structures may be necessary for holding musical phrases and passages in mind as part of making sense of a piece of music’s long-term structure.

"A novelty of our work is that we identified brain structures that track the temporal evolution of the music over extended periods of time, similar to our everyday experience of music listening," said postdoctoral scholar Daniel Abrams, PhD, the study’s first author.

The preferential activation of motor-planning centers in response to music, compared with pseudo-music, suggests that our brains respond naturally to musical stimulation by foreshadowing movements that typically accompany music listening: clapping, dancing, marching, singing or head-bobbing. The apparently similar activation patterns among normal individuals make it more likely our movements will be socially coordinated.

"Our method can be extended to a number of research domains that involve interpersonal communication. We are particularly interested in language and social communication in autism," Menon said. "Do children with autism listen to speech the same way as typically developing children? If not, how are they processing information differently? Which brain regions are out of sync?"

The age at which a child with autism is diagnosed is related to the particular suite of behavioral symptoms he or she exhibits, new research from the University of Wisconsin-Madison shows.

Certain diagnostic features, including poor nonverbal communication and repetitive behaviors, were associated with earlier identification of an autism spectrum disorder, according to a study in the April issue of the Journal of the American Academy of Child and Adolescent Psychiatry. Displaying more behavioral features was also associated with earlier diagnosis.

"Early diagnosis is one of the major public health goals related to autism," says lead study author Matthew Maenner, a researcher at the UW-Madison Waisman Center. "The earlier you can identify that a child might be having problems, the sooner they can receive support to help them succeed and reach their potential."

But there is a large gap between current research and what is actually happening in schools and communities, Maenner adds. Although research suggests autism can be reliably diagnosed by age 2, the new analysis shows that fewer than half of children with autism are identified in their communities by age 5.

One challenge is that autism spectrum disorders (ASD) are extremely diverse. According to the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition - Text Revision (DSM-IV-TR), the standard handbook used for classification of psychiatric disorders, there are more than 600 different symptom combinations that meet the minimum criteria for diagnosing autistic disorder, one subtype of ASD.

Previous research on age at diagnosis has focused on external factors such as gender, socioeconomic status, and intellectual disability. Maenner and his colleagues instead looked at patterns of the 12 behavioral features used to diagnose autism according to the DSM-IV-TR.

He and Maureen Durkin, a UW-Madison professor of population health and pediatrics and Waisman Center investigator, studied records of 2,757 8-year- olds from 11 surveillance sites in the nationwide Autism and Developmental Disabilities Monitoring Network, run by the Centers for Disease Control and Prevention (CDC). They found significant associations between the presence of certain behavioral features and age at diagnosis.

"When it comes to the timing of autism identification, the symptoms actually matter quite a bit," Maenner says.

In the study population, the median age at diagnosis (the age by which half the children were diagnosed) was 8.2 years for children with only seven of the listed behavioral features but dropped to just 3.8 years for children with all 12 of the symptoms.

The specific symptoms present also emerged as an important factor. Children with impairments in nonverbal communication, imaginary play, repetitive motor behaviors, and inflexibility in routines were more likely to be diagnosed at a younger age, while those with deficits in conversational ability, idiosyncratic speech and relating to peers were more likely to be diagnosed at a later age.

These patterns make a lot of sense, Maenner says, since they involve behaviors that may arise at different developmental times. The findings suggest that children who show fewer behavioral features or whose autism is characterized by symptoms typically identified at later ages may face more barriers to early diagnosis.

But they also indicate that more screening may not always lead to early diagnoses for everyone.

"Increasing the intensity of screening for autism might lead to identifying more children earlier, but it could also catch a lot of people at later ages who might not have otherwise been identified as having autism," Maenner says.

Most people are so attuned to the nuances of social interaction that they can detect clues to mental illness while playing a strategy game with someone they have never met.

That was the finding of a team of scientists led by Read Montague, director of the Human Neuroimaging Laboratory at the Virginia Tech Carilion Research Institute. The researchers discovered that healthy people and those with borderline personality disorder displayed different patterns of behavior while playing an online strategy game, so much so that when healthy players played people with borderline personality disorder, they gave up on trying to predict what their partners would do next.

For their large neuroimaging study, the scientists used a multiround social interaction game, the investor-trustee game, to study the level of strategic thinking in 195 pairs of subjects. In each pair, one player played the investor and the other the trustee. The investor chose how much money to send the trustee, and the trustee in turn decided how much to return to the investor. Profit required the cooperation of both players.

“This classic tit-for-tat game allows us to probe people’s responses to the social gestures of others,” said Montague, who also directs the Computational Psychiatry Unit, an academic center that uses computational models to understand mental disease. “It further allows us to see how people form models of one another. These insights are important for understanding a range of mental illnesses, as the ability to infer other people’s intentions is an essential component of healthy cognition.”

The scientists classified the investors according to varying levels of strategic depth of thought. The healthy subjects fell into three categories: about half simply responded to the amount the other player sent; about one-quarter built a model of their partner’s behavior; and the remaining quarter considered not just their model of their partner, but also their partner’s models of them. 

Not surprisingly, the depth-of-thought style of play correlated with success, with the players who looked deeper into interactions making considerably more money than those who played at a shallow level.

When healthy subjects played people with borderline personality disorder, though, they were far less likely to exhibit depth of thought.

“People with borderline personality disorder are characterized by their unstable relationships, and when they play this game, they tend to break cooperation,” said Montague. “The healthy subjects picked up on the erratic behavior, likely without even realizing it, and far fewer played strategically.”

Notably, the functional magnetic resonance imaging of the subjects’ brains revealed that each category of player showed distinct neural correlates of learning signals associated with differing depths of thought. The scientists used hyperscanning, a technique Montague invented that enables subjects in different brain scanners to interact in real time, regardless of geography. Hyperscanning allows scientists to eavesdrop on brain activity during social exchanges in scanners, whether across the hallway or across the world.

“We’re always modeling other people, and our brains have a substantial amount of neural tissue devoted to pondering our interactions with other people,” Montague said. “This study is a start to turning neural signals into numbers – not just theory-of-mind arguments, but actual numbers. And when we can do that across thousands of people, we should start to gain insights into psychopathologies – what circuits are involved, what brain regions are engaged, and how injuries, congenital disorders, and genetic defects might play into psychiatric illness.”

Montague believes the study represents a significant contribution to the field of computational psychiatry, which seeks to bring computational clout to efforts to understand mental dysfunction. “Traditional psychiatric categories are useful yet incomplete,” said Montague, who delivered a TEDGlobal talk on the growing field of computational psychiatry last year. “Computational psychiatry enables us to redefine with a new lexicon – a mathematical one – the standard ways we think about mental illness.”

Computationally based insights may one day help psychiatry achieve better precision in diagnosis and treatment, Montague said. But until scientists have the right instruments, they cannot even begin to make those connections.

“The exquisite sensitivity that most people have to social gestures gives us a valuable opening,” Montague said. “We’re hoping to invent a tool – almost a human inkblot test – for identifying and characterizing mental disorders in which social interactions go awry.”

Newborn babies’ immune system development and levels of vitamin D have been found to vary according to their month of birth, according to new research.

The research, from scientists at Queen Mary, University of London and the University of Oxford, provides a potential biological basis as to why an individual’s risk of developing the neurological condition multiple sclerosis (MS) is influenced by their month of birth. It also supports the need for further research into the potential benefits of vitamin D supplementation during pregnancy.

Around 100,000 people in the UK have MS, a disabling neurological condition which results from the body’s own immune system damaging the central nervous system. This interferes with the transmission of messages between the brain and other parts of the body and leads to problems with vision, muscle control, hearing and memory. 

The development of MS is believed to be a result of a complex interaction between genes and the environment.

A number of population studies have suggested that the month you are born in can influence your risk of developing MS. This ‘month of birth’ effect is particularly evident in England, where the risk of MS peaks in individuals born in May and drops in those delivered in November. As vitamin D is formed by the skin when it is exposed to sunlight, the ‘month of birth’ effect has been interpreted as evidence of a prenatal role for vitamin D in MS risk.

In this study, samples of cord blood – blood extracted from a newborn baby’s umbilical cord – were taken from 50 babies born in November and 50 born in May between 2009 and 2010 in London.

The blood was analysed to measure levels of vitamin D and levels of autoreactive T-cells. T-cells are white blood cells which play a crucial role in the body’s immune response by identifying and destroying infectious agents, such as viruses. However some T-cells are ‘autoreactive’ and capable of attacking the body’s own cells, triggering autoimmune diseases, and should be eliminated by the immune system during its development. This job of processing T-cells is carried out by the thymus , a specialised organ in the immune system located in the upper chest cavity.

The results showed that the May babies had significantly lower levels of vitamin D (around 20 per cent lower than those born in November) and significantly higher levels (approximately double) of these autoreactive T-cells, compared to the sample of November babies.

Co-author Dr Sreeram Ramagopalan, a lecturer in neuroscience at Barts and The London School of Medicine and Dentistry, part of Queen Mary, said: “By showing that month of birth has a measurable impact on in utero immune system development, this study provides a potential biological explanation for the widely observed “month of birth” effect in MS. Higher levels of autoreactive T-cells, which have the ability to turn on the body, could explain why babies born in May are at a higher risk of developing MS.

“The correlation with vitamin D suggests this could be the driver of this effect. There is a need for long-term studies to assess the effect of vitamin D supplementation in pregnant women and the subsequent impact on immune system development and risk of MS and other autoimmune diseases.”

The research letter is published today in the journal JAMA Neurology.