July 12, 2012

Biologists at UC San Diego have discovered a chemical that offers a completely new and promising direction for the development of drugs to treat metabolic disorders such as type 2 diabetes—a major public health concern in the United States due to the current obesity epidemic.

Their discovery, detailed in a paper published July 13 in an advance online issue of the journal Science, initially came as a surprise because the chemical they isolated does not directly control glucose production in the liver, but instead affects the activity of a key protein that regulates the internal mechanisms of our daily night and day activities, which scientists call our circadian rhythm or biological clock.

Scientists had long suspected that diabetes and obesity could be linked to problems in the biological clock. Laboratory mice with altered biological clocks, for example, often become obese and develop diabetes. Two years ago, a team headed by Steve Kay, dean of the Division of Biological Sciences at UC San Diego, discovered the first biochemical link between the biological clock and diabetes. It found that a key protein, cryptochrome, that regulates the biological clocks of plants, insects and mammals also regulates glucose production in the liver and that altering the levels of this protein could improve the health of diabetic mice.

Now Kay and his team have discovered a small molecule—one that can be easily developed into a drug—that controls the intricate molecular cogs or timekeeping mechanisms of cryptochrome in such a manner that it can repress the production of glucose by the liver. Like mice and other animals, humans have evolved biochemical mechanisms to keep a steady supply of glucose flowing to the brain at night, when we’re not eating or otherwise active.

"At the end of the night, our hormones signal that we’re in a fasting state," said Kay. "And during the day, when we’re active, our biological clock shuts down those fasting signals that tell our liver to make more glucose because that’s when we’re eating."

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ScienceDaily (July 11, 2012) — Widely held beliefs about Neuro-Linguistic Programming and lying are unfounded.

Twenty portrait of a woman with different expressions. (Credit: © gemenacom / Fotolia)

Proponents of Neuro-Linguistic Programming (NLP) have long claimed that it is possible to tell whether a person is lying from their eye movements.  Research published July 11 in the journal PLoS ONE reveals that this claim is unfounded, with the authors calling on the public and organisations to abandon this approach to lie detection.

For decades many NLP practitioners have claimed that when a person looks up to their right they are likely to be lying, whilst a glance up to their left is indicative of telling the truth.

Professor Richard Wiseman (University of Hertfordshire, UK) and Dr Caroline Watt (University of Edinburgh, UK) tested this idea by filming volunteers as they either lied or told the truth, and then carefully coded their eye movements.  In a second study another group of participants was asked to watch the films and attempt to detect the lies on the basis of the volunteers’ eye movements.

"The results of the first study revealed no relationship between lying and eye movements, and the second showed that telling people about the claims made by NLP practitioners did not improve their lie detection skills,” noted Wiseman. 

A final study involved moving out of the laboratory and was conducted in collaboration with Dr Leanne ten Brinke and Professor Stephen Porter from the University of British Columbia, Canada.  The team analysed films of liars and truth tellers from high profile press conferences in which people were appealing for missing relatives or claimed to have been the victim of a crime. 

"Our previous research with these films suggests that there are significant differences in the behaviour of liars and truth tellers," noted Dr Leanne ten Brinke. "However, the alleged tell-tale pattern of eye movements failed to emerge."

"A large percentage of the public believes that certain eye movements are a sign of lying, and this idea is even taught in organisational training courses.  Our research provides no support for the idea and so suggests that it is time to abandon this approach to detecting deceit" remarked Watt.

Source: Science Daily

ScienceDaily (July 11, 2012) — When humans learn, their brains relate new information with past experiences to derive new knowledge, according to psychology research from The University of Texas at Austin.

The study, led by Alison Preston, assistant professor of psychology and neurobiology, shows this memory-binding process allows people to better understand new concepts and make future decisions. The findings could lead to better teaching methods, as well as treatment of degenerative neurological disorders, such as dementia, Preston says.

"Memories are not just for reflecting on the past; they help us make the best decisions for the future," says Preston, a research affiliate in the Center for Learning and Memory, which is part of the university’s College of Natural Sciences. "Here, we provide a direct link between these derived memories and the ability to make novel inferences."

The paper was published online in July in the journal Neuron. The authors include University of Texas at Austin researchers Dagmar Zeithamova and April Dominick.

In the study, 34 subjects were shown a series of paired images composed of different elements (for example, an object and an outdoor scene). Each of the paired images would then reappear in more presentations. A backpack, paired with a horse in the first presentation, would appear alongside a field in a later presentation. The overlap between the backpack and outdoor scenery (horse and field) would cause the viewer to associate the backpack with the horse and field. The researchers used this strategy to see how respondents would delve back to a recent memory while processing new information.

Using functional Magnetic Resonance Imaging (fMRI) equipment, the researchers were able to look at the subjects’ brain activity as they looked at image presentations. Using this technique, Preston and her team were able to see how the respondents thought about past images while looking at overlapping images. For example, they studied how the respondents thought about a past image (a horse) when looking at the backpack and the field. The researchers found the subjects who reactivated related memories while looking at overlapping image pairs were able to make associations between individual items (i.e. the horse and the field) despite the fact that they had never studied those images together.

To illustrate the ways in which this cognitive process works, Preston describes an everyday scenario.

Imagine you see a new neighbor walking a Great Dane down the street. At a different time and place, you may see a woman walking the same dog in the park. When experiencing the woman walking her dog, the brain conjures images of the recent memory of the neighbor and his Great Dane, causing an association between the dog walkers to be formed in memory. The derived relationship between the dog walkers would then allow you to infer the woman is also a new neighbor even though you have never seen her in your neighborhood.

"This is just a simple example of how our brains store information that goes beyond the exact events we experience," Preston says. "By combining past events with new information, we’re able to derive new knowledge and better anticipate what to expect in the future."

During the learning tasks, the researchers were able to pinpoint the brain regions that work in concert during the memory-binding process. They found the hippocampal-ventromedial prefrontal cortex (VMPFC) circuit is essential for binding reactivated memories with current experience.

Source: Science Daily

July 11, 2012

Two powerful brain chemical systems work together to paralyze skeletal muscles during rapid eye movement (REM) sleep, according to new research in the July 11 issue of The Journal of Neuroscience. The finding may help scientists better understand and treat sleep disorders, including narcolepsy, tooth grinding, and REM sleep behavior disorder.

During REM sleep — the deep sleep where most recalled dreams occur — your eyes continue to move but the rest of the body’s muscles are stopped, potentially to prevent injury. In a series of experiments, University of Toronto neuroscientists Patricia L. Brooks and John H. Peever, PhD, found that the neurotransmitters gamma-aminobutyric acid (GABA) and glycine caused REM sleep paralysis in rats by “switching off” the specialized cells in the brain that allow muscles to be active. This finding reversed earlier beliefs that glycine was a lone inhibitor of these motor neurons.

"The study’s findings are relevant to anyone who has ever watched a sleeping pet twitch, gotten kicked by a bed partner, or has known someone with the sleep disorder narcolepsy," said Dennis J. McGinty, PhD, a behavioral neuroscientist and sleep researcher at the University of California, Los Angeles, who was not involved in the study. "By identifying the neurotransmitters and receptors involved in sleep-related paralysis, this study points us to possible molecular targets for developing treatments for sleep-related motor disorders, which can often be debilitating," he said

The researchers measured electrical activity in the facial muscles responsible for chewing of sleeping rats. Brain cells called trigeminal motor neurons communicate the brain’s message to move to these muscles. Previous research suggested neurotransmitter receptors called ionotropic GABAA/glycine receptors in the motor neurons caused REM sleep paralysis. However, when the researchers blocked these receptors, REM sleep paralysis still occurred.

The researchers found that to prevent REM sleep paralysis, they had to block both the ionotropic receptors and metabotropic GABAB receptors, a different receptor system. In other words, when the motor cells were cut off from all sources of GABA and glycine, the paralysis did not occur, allowing the rats to exhibit high levels of muscle activity when their muscles should have been inactive. The data suggest the two neurotransmitters must both be present together to maintain motor control during sleep, rather than working separately.

The finding could be especially helpful for those with REM sleep disorder, a disease that causes people to act out their dreams. This can cause serious injuries to patients and others around them. It is also often an early indicator of neurodegenerative diseases, such as Parkinson’s.

"Understanding the precise mechanism behind these chemicals’ role in REM sleep disorder is particularly important because about 80 percent of people who have it eventually develop a neurodegenerative disease, such as Parkinson’s disease," study author Peever added. "REM sleep behavior disorder could be an early marker of these diseases, and curing it may help prevent or even stop their development,” he said.

Provided by University of Toronto

Source: medicalxpress.com

July 11, 2012

A new study shows that taking part in a stress management program may help people with multiple sclerosis (MS) prevent new disease activity. The study is published in the July 11, 2012, online issue of Neurology, the medical journal of the American Academy of Neurology.

A weekly stress management program for patients with multiple sclerosis (M.S.) prevented the development of new brain lesions, a marker of the disease’s activity in the brain, according to new Northwestern Medicine research. Brain lesions in M.S. often precede flare-ups of symptoms such as loss of vision or use of limbs or pain.

"This is the first time counseling or psychotherapy has been shown to affect the development of new brain lesions," said David Mohr, principal investigator of the study and professor of preventive medicine at Northwestern University Feinberg School of Medicine. "In M.S., the prevention of new brain lesions is an important marker used to judge how effective medications are."

"The new finding is an important step and the strongest evidence we have to date that stress is involved in M.S.," Mohr added.

The results indicate that stress management therapy may be a useful adjunct treatment with drug therapy for M.S., but a larger clinical trial is needed to confirm this, Mohr said.

The study is published in the July 11, 2012 issue of Neurology, the medical journal of the American Academy of Neurology.

Mohr’s previous research showed a connection between psychological distress and the development of new brain lesions. Stress is one of many factors, he said, that influence whether the underlying M.S. disease processes escalate to the point of a new lesion or a relapse. Mohr has spent more than a decade studying the link between emotional distress, including a study on depression, and M.S.

For an event to be stressful, a person has to feel it is a threat to something important, and that he or she doesn’t have any control over it.

"We taught patients strategies to evaluate how much of a threat something truly is," Mohr said. "When people overestimate the threat of an event or underestimate their ability to manage it, we teach them how to evaluate their own thinking about the stress and how to challenge and change that thinking to a more realistic and helpful appraisal of the actual threat. That often leads to improved ability to manage stressful events."

Patients also were taught how to calm their physical reactions to stress through relaxation and meditation to cope with stressful events that couldn’t be avoided.

In the national clinical trial, 121 patients were randomized to receive stress management therapy for M.S. or be in a control group. Those in the therapy group received 16 sessions over a 24-week period during which they were taught coping skills to enhance their ability to prevent stressful events from occurring and to improve their capacity to manage their responses to stressful events that did arise. They also received a 24-week post-treatment follow-up. Two-thirds of the patients were women, who have a higher incidence of M.S.

MRI neuroimaging showed the stress management therapy reduced two types of new brain lesions common in multiple sclerosis.

The first type, gadolinium-enhancing brain lesions, indicates a breakdown of the blood-brain barrier, allowing the immune system access to attack and damage brain cells. Gadolinium is injected into an M.S. patient during the MRI and can be observed passing through the blood-brain barrier, if these types of lesions are present. These lesions may disappear over time or may leave more permanent damage in the brain.

The second type, a T2 brain lesion, is a more global marker of the effect of M.S. on the brain and is a more permanent lesion. These markers are commonly used in evaluating M.S. medications in Phase II trials. If the lesions are decreased, the implication is the drug is working.

Among patients who received stress management therapy, 55 percent had a new gadolinium-enhancing brain lesion during the treatment period, compared to 77 percent of those in the control group. Similarly, 43 percent receiving stress management therapy had a new T2 brain lesion during the treatment period, compared to 70 percent in the control group. The stress reduction prevented new lesions whether or not the patients were taking M.S. disease-modifying medications (e.g., beta-interferons or glatiramer acetate).

But the improvement in brain lesions didn’t last after the stress management program ended.

"This suggests that we will need to develop treatments that are more sustainable over longer periods of time," Mohr said. "It’s difficult for people to come in for treatment once a week over long periods of time, due both to cost and time constraints. We are looking at telemedicine programs that can be delivered via a computer or a smartphone to people in their environment at much lower costs than traditional therapy."

The study did not show a statistical difference in the rate of clinical M.S. symptoms, but Mohr said he didn’t expect one in such a small number of participants. The outcome goal of this trial was only to see if the stress reduction affected the brain lesions.

While the results are positive, Mohr said, it’s premature to make recommendations for patients regarding use of stress management therapy. “I don’t want to see patients decide not to take their medication and use this instead,” he emphasized.

Provided by American Academy of Neurology

Source: medicalxpress.com

July 11, 2012

Communication between the brain and muscle must be strong for us to eat, breathe or walk. Now scientists have found that a protein known to be on the surface of muscle cells must be present in both tissues to ensure the conversation is robust.

Communication between the brain and muscle must be strong for us to eat, breathe or walk. Now scientists have found that a protein known to be on the surface of muscle cells must be present in both tissues to ensure the conversation is robust. Credit: Phil Jones

Scientists at the Medical College of Georgia at Georgia Health Sciences University have shown that without LRP4 in muscle cells and neurons, communication between the two cells types is inefficient and short-lived.

Problems with the protein appear to contribute to disabling disorders such as myasthenia gravis and other forms of muscular dystrophy. The MCG scientists reported finding antibodies to LRP4 in the blood of about 2 percent of patients with muscle-degenerating myasthenia gravis in Archives of Neurology earlier this year.

Scientists know that LRP4 plays an important role in the muscle cell, where it receives cues from the brain cell that it’s time to form the receptors that will be enable ongoing communication between the two, said Dr. Lin Mei, Director of the GHSU Institute of Molecular Medicine and Genetics and corresponding author of the study in the journal Neuron.

However when Dr. Haitao Wu deleted LRP4 just from muscle cells, a connection – albeit a weak one – still formed between muscle and brain cells. The mice survived several days during which they experienced some of the same muscle weakness as patients with myasthenia gravis. “That’s against the dogma,” Mei said. “If LRP4 is essential only in the muscle cells, how could the mice survive?” When they totally eliminated LRP4, neuromuscular junctions never formed and the mice didn’t survive.

Additional evidence suggests that LRP4 in the neurons is vital, said Wu, postdoctoral fellow and the study’s first author. “When we knocked out the LRP4 gene in the muscles, there was some redundant function coming from the motor neuron, like a rescue attempt,” he said. They documented the neuron reaching out to share LRP4 with the muscle cell. Unfortunately, the gesture was not sufficient.

"The nerve does not get the stop signal," Mei said, referencing images of too-long neurons that never got the message from the muscle that they have gone far enough. When they cut the elongated nerves, they found they didn’t contain enough vesicles, little packages of chemical messengers that are the hallmark of brain cell communication. On the receiving end, muscle cells developed receptors that were too small and too few – hence, the tenuous communication network. "When LRP4 in the muscle is taken out, not surprisingly, the muscle has some kind of a problem," Mei said. "What was very surprising was that the motor neurons also have problems.”

"The talk between motor neurons and muscle cells is very critical to the synapse formation and the very precise action between the two," Wu said. Mei’s lab earlier established that the conversation goes both ways.

The scientists believe about 60 percent of the LRP4 comes from muscle cells, about 20 percent from brain cells – which helps explain why the brain’s effort to share is insufficient – and the remainder from cells in spaces between the two. In addition to better explaining nerve-muscle communication, the scientists hope their findings will eventually enable gene therapy that delivers LRP4 to bolster insufficient levels in patients.

Other early and key players in establishing nerve-muscle conversation include agrin, a protein that motor neurons release to direct construction of the synapse, a sort of telephone line between the nerve and muscle. MuSK on the muscle cell surface initiates critical internal cell talk so synapses can form and receptors that enable specific commands will cluster at just the right spot.

Mei’s lab reported in Neuron in 2008 that agrin starts talking with LRP4 on the muscle cell surface, then recruits the enzyme MuSK to join the conversation. LRP4 and MuSK become major components of the receptor needed for the muscle cell to receive the message agrin is sending.

The agrin-MuSK signaling pathway has been implicated in muscular dystrophy, a group of genetic diseases that lead to loss of muscle control because of problems with neurons, muscle cells and/or their communication. Some reports have implicated a mutant MuSK as a cause of muscular dystrophy and autoantibodies (antibodies the body makes against itself) to MuSK have been found in the blood of some patients.

Provided by Georgia Health Sciences University

Source: medicalxpress.com

July 11, 2012

An inflated sense of memory function in people with dementia may influence their likelihood of seeking help, new Flinders University research shows.

As part of her PhD, Flinders research associate Dr. Chris Materne studied the disparity between memory perception and performance in people with dementia.

In the first stage of the project, Dr. Materne analysed data from the Australian Longitudinal Study of Aging which showed that most survey participants believed their memory had remained stable over the 11-year assessment, despite tests showing a decline in memory performance.

She then conducted an intervention with 13 individuals, from a larger group of 23 people with dementia, using spaced retrieval memory training to help them achieve a specific task or activity, such as remembering to lock the front door or keep their glasses in the same spot.

“Spaced retrieval works by helping people remember specific information or tasks by getting them to respond to a prompt question over progressively increasing intervals of time,” Dr. Materne said.

“In one case we helped a man remember to put his glasses in the same place because he was always losing them which made both him and his wife quite distressed,” she said.

“We think the training taps into procedural memory so it becomes habitual rather than explicit memory, such as memory for facts, which tends to decline before procedural memory when you have dementia.”

The technique was conducted once a week for six weeks, with seven out of the 13 participants still able to perform their nominated activity or task after six months.

The 23 participants were also asked to rate their performance based on a specific question, such as how many people they could name in a photo with 10 faces.

While most respondents were initially over-confident in their abilities, with some claiming to be able to name all 10 faces, their perceptions did change over time to more accurately reflect their cognitive function.

About one third of family carers, however, initially considered their loved ones memory to be better than what the person with dementia actually reported.

“In the longitudinal sample people didn’t feel their memory had changed over time because the questions were more general but when we asked specific, detailed questions about memory in the smaller study, the respondents came to recognise their declining performance.”

Dr. Materne said the research highlighted the need for more comprehensive assessments when diagnosing dementia to increase the accuracy of peoples’ perceptions, and therefore their likelihood of seeking help.

Provided by Flinders University

Source: medicalxpress.com

ScienceDaily (July 11, 2012) — Stanford University School of Medicine scientists have laid bare a novel molecular mechanism responsible for the most important symptom of major depression: anhedonia, the loss of the ability to experience pleasure. While their study was conducted in mice, the brain circuit involved in this newly elucidated pathway is largely identical between rodents and humans, upping the odds that the findings point toward new therapies for depression and other disorders.

Additionally, opinion leaders hailed the study’s inventive methodology, saying it may offer a much sounder approach to testing new antidepressants than the methods now routinely used by drug developers.

While as many as one in six Americans is likely to suffer a major depression in their lifetimes, current medications either are inadequate or eventually stop working in as many as 50 percent of those for whom they’re prescribed.

"This may be because all current medications for depression work via the same mechanisms," said Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. "They increase levels of one or another of two small molecules that some nerve cells in the brain use to signal one another. To get better treatments, there’s a great need to understand in greater detail the brain biology that underlies depression’s symptoms." The study’s first author is Byung Kook Lim, PhD, a postdoctoral scholar in Malenka’s laboratory.

Malenka is senior author of the new study, published July 12 in Nature, which reveals a novel drug target by showing how a hormone known to affect appetite turns off the brain’s ability to experience pleasure when an animal is stressed. This hormone, melanocortin, signals to an ancient and almost universal apparatus deep in the brain called the reward circuit, which has evolved to guide animals toward resources, behaviors and environments — such as food, sex and warmth — that enhance their prospects for survival.

"This is the first study to suggest that we should look at the role of melanocortin in depression-related syndromes," said Eric Nestler, MD, PhD, professor and chair of neuroscience and director of the Friedman Brain Institute at Mount Sinai School of Medicine in New York. Nestler was not involved in the study but is familiar with its contents.

Read more …

ScienceDaily (July 11, 2012) — In the current online issue of PLoS ONE, researchers at the University of California, San Diego School of Medicine say they have identified a set of laboratory-based biomarkers that can be useful for understanding brain-based abnormalities in schizophrenia. The measurements, known as endophenotypes, could ultimately be a boon to clinicians who sometimes struggle to recognize and treat the complex and confounding mental disorder.

"A major problem in psychiatry is that there are currently no laboratory tests that aid in diagnosis, guide treatment decisions or help predict treatment response or outcomes," said Gregory A. Light, PhD, associate professor of psychiatry and the study’s first author. "Diagnoses are currently based on a clinician’s ability to make inferences about patients’ inner experiences."

Diagnosing and treating schizophrenia is a particularly troubling challenge. The disorder, which affects about 1 percent of the U.S. population or roughly 3 million people, is characterized by a breakdown of normal thought processes and erratic, sometimes dangerous or harmful, behaviors.

"Schizophrenia is among the most severe and disabling conditions across all categories of medicine," said Light, who also directs the Mental Illness, Research, Education and Clinical Center at the San Diego VA Healthcare System.

The precise cause or causes of schizophrenia are not known, though there is a clear genetic component, with the disorder more common in some families.

Clinicians typically diagnose schizophrenia based upon inferences drawn from the patient’s inner experiences. That is, their ability to describe what’s happening inside their minds.

"But even the best clinicians struggle with diagnostic complexities based on sometimes fuzzy clinical phenomenology," said Light. The clinical challenge is compounded by the fact that "many schizophrenia patients have cognitive and functional impairments," said Light. They may not be able to reasonably explain how or what they think.

Light and colleagues investigated whether a select battery of neurophysiological and neurocognitive biomarkers could provide clinicians with reliable, accurate, long-term indicators of brain dysfunction, even when overt symptoms of the disorder were not apparent. These markers ranged from tests of attention and memory to physiological assessments of basic perceptual processes using scalp sensors to measure brain responses to simple sounds.

The researchers measured the biomarkers in 550 schizophrenia patients, and then re-tested 200 of the patients one year later. They found that most of the markers were significantly abnormal in schizophrenia patients, were relatively stable between the assessments and were not affected by modest fluctuations in clinical status of the patient.

Light said further research is required, including whether the endophenotypes can differentiate other psychiatric disorders, be used to anticipate patient response to different kinds of drugs or non-pharmacological interventions or even be used to predict which subjects are at high risk of developing a psychotic illness.

"We believe this paper is an important step towards validating laboratory-based biomarkers for use in future genomic and clinical treatment studies of schizophrenia," Light said.

Source: Science Daily