Neuroscience

June 28, 2012

In a genome-wide association (GWA) study, researchers from Boston University Schools of Medicine (BUSM) and Public Health (BUSPH) have identified several genes which influence degeneration of the hippocampus, the part of the brain most associated with Alzheimer disease (AD). The study, which currently appears online as a Rapid Communication in the Annals of Neurology, demonstrates the efficacy of endophenotypes for broadening the understanding of the genetic basis of and pathways leading to AD.

AD is a progressive neurodegenerative disorder for which there are no prevention methods. Available drugs only marginally affect disease severity and progression, making AD effectively untreatable.

GWA studies using very large samples have increased the number of robust associations to 10 genes, including APOE. However, these genes account for no more than 35 percent of the inherited risk of AD and most of the genetic underpinning of the disorder remains unexplained. According to the researchers, magnetic resonance imaging (MRI) of the brain provides in vivo quantitative measures of neurodegenerative and cerebrovascular brain injury that may represent AD-related changes long before clinical symptoms appear. These measures are more powerful than comparisons of individuals with AD with cognitively healthy persons because they avoid misclassification of normal persons who will develop disease in the future.

BUSM researchers conducted a two-stage GWA study for quantitative measures of hippocampal volume (HV), total cerebral volume (TCV) and white matter hyperintensities (WMH). Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African-American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer’s Genetic Epidemiology) Study. In addition, similar MRI measures were obtained from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls (all Caucasian) in the AD Neuroimaging Initiative (ADNI) Study. The MIRAGE Caucasian families and ADNI subjects were included in the first stage and the MIRAGE African American families were added in stage two. Results from the two Caucasians data sets were combined by meta-analysis.

In stage two, one genetic marker (i.e. single nucleotide polymorphism or SNP) from each of the gene regions that were most significantly associated with AD in the Caucasian data sets was evaluated in the African-American data set.

Novel genome-wide significant associations were observed for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set.

"Our two-stage GWAS identified highly significant associations between a measure of degeneration in the brain region most strongly correlated with AD and several genes in both Caucasian and African American samples containing AD, cognitively impaired and cognitively healthy subjects. One of these associations was with the ε4 variant of APOE which is the most well-established genetic risk factor for AD.

Other associations were demonstrated with markers in F5/SELP, LHFP, and GCFC2, genes not previously implicated in this disease” explained senior author Lindsay Farrer, PhD, chief of biomedical genetics at BUSM. He also noted, “previous studies showed that blood level of P-selectin (the protein encoded by SELP) has been correlated with rate of cognitive decline in AD patients.”

Farrer believes it is very likely that the number and specificity of these associations will increase in future studies using larger samples and focused on additional precise structural and functional MRI measures. “These findings will inform experiments designed to increase our understanding of disease-causing mechanism and may lead to new therapeutics targets,” added Farrer.

Provided by Boston University Medical Center

Source: medicalxpress.com

June 28, 2012

In a process akin to belling an infinitesimal cat, scientists have managed to tag a protein that regulates the neurotransmitter serotonin with tiny fluorescent beads, allowing them to track the movements of single molecules for the first time.

This is a microphotograph of neurons with their serotonin transporter protein labeled with red quantum dots. Credit: Jerry Chang, Vanderbilt University

The capability, which took nearly a decade to achieve, makes it possible to study the dynamics of serotonin regulation at a new level of detail, which is important because of the key role that serotonin plays in the regulation of mood, appetite and sleep.

The achievement was reported by an interdisciplinary team of Vanderbilt scientists in the June 27 issue of the Journal of Neuroscience.

The regulatory protein that the scientists successfully tagged is known as the serotonin transporter. This is a protein that extends through the membrane that forms the nerve’s outer surface and acts like a nano-sized vacuum cleaner that sucks serotonin molecules into the cell body and away from serotonin target receptors on other cells. In this fashion it helps regulate the concentration of serotonin in the area around the cell. Serotonin transporters are an important research subject because they are the target for the most common drugs used to treat depression, including Prozac, Paxil and Lexapro.

"If you are interested in mental health, then serotonin transporters are an ideal subject," said Sandra Rosenthal, the Jack and Pamela Egan Chair of Chemistry, who directed the study with Randy Blakely, the Allan D. Bass Professor of Pharmacology and Psychiatry.

Problems with serotonin transporter regulation have also been implicated in autism. Two years ago, Blakely and geneticist James Sutcliffe, associate professor of molecular physiology and biophysics, reported the discovery of multiple changes in the serotonin transporter protein that cause the transporter to become “overactive” in subjects with autism. Recently, Blakely and Assistant Professor of Psychiatry Jeremy Veenstra-VanderWeele reported that mice expressing one of these high-functioning transporters exhibit multiple behavioral changes that resemble changes seen in kids with autism.

The brain’s other key neurotransmitters have their own transporter proteins, so scientists can use the capability to track the motion of individual transporter molecules to determine how they are regulated as well.

Attempts to understand how these transporters work have been limited by the difficulty of studying their dynamic behavior. “In the past, we have been limited to snapshots that show the location of transporter molecules at a specific time,” said chemistry graduate student Jerry Chang, who developed the tagging technique. “Now we can follow their motion on the surface of cells in real time and see how their movements relate to serotonin uptake activity.”

The fluorescent tags that the researchers used are nanoscale beads called quantum dots made from a mixture of cadmium and selenium. These beads are only slightly bigger than the proteins they are tagging: You would have to string 10,000 together to span the width of a human hair.

Quantum dots emit colored light when illuminated and have the useful property that small changes in their size cause them to glow in different colors. Team member Ian D. Tomlinson, assistant research professor of chemistry, developed a special molecular string that attaches to the quantum dot at one end and, on the other end, attaches to a drug derivative that binds exclusively with the serotonin transporter. When a mixture that contains these quantum dots is incubated with cultured nerve cells, the drug attaches to the transporter. As the protein moves around, it drags the quantum dot behind it like a child holding a balloon on a string. When the area is illuminated, the quantum dots show up in a microscope as colored points of light.

"Until now, neurobiologists have had to rely on extremely low resolution approaches where it takes the signals coming from thousands to millions of molecules to be detected," said Blakely, "We really had no idea exactly what we were going to see."

Putting their new procedure to use, the researchers looked at extensions of the nerve cell that are involved in secreting serotonin on the presumption that transporters would be localized there as well. From previous research, the investigators suspected that the transporters would be concentrated in cholesterol-rich parts of these extensions, termed rafts, although the level of resolution with standard approaches was inadequate to provide any clues as to what they were doing there.

The quantum dot studies demonstrated that there were two distinct populations of transporters in these areas: Those that can travel freely around the membrane and those that act as if they are unable to move. They found that the immobile transporters were located in the rafts. When they stimulated the cell to increase transporter activity, they were surprised at what happened. “We found that the transporters in the rafts began to move much faster whereas the motion of the other population didn’t change at all,” Rosenthal reported. Since the mobilized transporters do not leave the rafts, they appear to whizz around inside a confined compartment, as if released from chains that normally keep them subdued. These observations suggest it is likely that the two populations are controlled by different regulatory pathways.

"Now that we can watch transporter regulation actually happening, we should be able to figure out the identity of the anchoring proteins and the signals these proteins respond to that permit transporters to switch back and forth between low and high activity levels," said Blakely.

"Currently, antidepressant drugs must fully shut down the brain’s serotonin transporters to achieve a clinical benefit," the pharmacologist said. Such a manipulation can produce a number of unpleasant side-effects, such as nausea, weight gain, sexual problems, fatigue and drowsiness.

"By understanding the basic mechanisms that naturally turn serotonin transporter activity up and down, maybe we can develop medications that produce milder side-effects and have even greater efficacy," he said. "Our sights are also focused on transferring what we have learned with normal serotonin transporters to an understanding of the hyperactive transporters we have found in kids with autism.”

Provided by Vanderbilt University

Source: medicalxpress.com

June 28, 2012

(Medical Xpress) — New research has shed light on the high risk of fractures, falls, and osteoporosis among epilepsy patients using antiepileptic drugs with most patients unaware of the risks associated with taking the drugs.

The study led by the University of Melbourne and published in the prestigious Neurology journal, found that people taking antiepileptic drugs are up to four times more likely to suffer spine, collarbone and ankle fractures and are more likely to have been diagnosed with osteoporosis.

The study also revealed that these patients are more than four times as likely as non-users of antiepileptic drugs to have been diagnosed with osteoporosis.

In addition, treatment affected balance with results showing almost double the falls rate in female patients taking the medication compared with non-users.

Chief Investigator, Prof John Wark from the University of Melbourne’s Department of Medicine at the Royal Melbourne Hospital said this research revealed new information critical to understanding the higher risk for fractures and falls in epilepsy patients taking antiepileptic medication.

“We believe patients need to be offered better information to help them to avoid these risks and prevent injury,” he said.

More than 70 percent of epilepsy patients who participated in the study were unaware of the increased risk of fractures, decreased bone mineral density and falls associated with taking antiepileptic medications.

“No published studies have explored epilepsy patients’ awareness of the effects of AEDs on bone health, fracture risk and falls.  This study indicates that awareness of these issues is poor, despite our study population attending specialist epilepsy clinics at a centre with a major interest in this area,” said Prof Wark.

“Most patients indicated they would like to be better informed about these issues, suggesting that more effective education strategies are warranted and would be well-received.”

“Epilepsy patients should be assessed regularly for their history of falls and fractures for appropriate management strategies to be offered.”

The study compared 150 drug users with 506 non-users.  All drug users were epilepsy outpatients at the Royal Melbourne Hospital, over 15 years old and had been taking AEDs for a minimum of three months.

Provided by University of Melbourne

Source: medicalxpress.com

ScienceDaily (June 27, 2012) — Modern anesthesia is extremely safe. But as risks to heart, lungs and other organs have waned, another problem has emerged in the elderly: post-operative cognitive dysfunction. Mentally, some patients “just aren’t the same” for months or longer after surgery. Other factors play a role, but a small number of patients deteriorate mentally due to anesthesia per se. Those with Alzheimer’s disease suffer exacerbations, and those without the diagnosis may have it unmasked by anesthesia, suggesting some relationship.

Alzheimer’s disease has two types of brain lesions. Beta-amyloid deposits accumulate outside neurons but don’t cause cognitive problems. Neurofibrillary tangles inside neurons, composed of hyper-phosphorylated ‘tau’, a protein normally attached to microtubules, do correlate with dementia. These same tau tangles are found in post-anesthesia dementia.

Microtubules (MTs) polymerize from ‘tubulin’ proteins to grow, shape and regulate neurons. Synaptic components are transported by motor proteins which move like railroad trains along MT tracks. In branching dendrites, motors change MTs repeatedly to reach their destination. Tau is a traffic signal, telling motors where to get on and off, the route encoded in MT binding sites for tau.

That MTs process information stems from Charles Sherrington in the 1950s, with recent controversial suggestions of MT computing, and even quantum computing mediating consciousness and memory. But whether MTs play a primary, or mere supportive role, their stability and function are essential to cognition and consciousness.

Excessive phosphorylation had been thought the culprit in detaching tau and causing tangles. But destabilized MTs now appear to be the primary problem in both Alzheimer’s and post-anesthesia dementia, releasing tau which then becomes hyperphosphorylated. Anesthetics are known to bind to tubulin, in some cases for days after exposure, and in high doses to cause MT disassembly.

Now, in a study in PLoS ONE, a team from Canada, Portugal and the USA report molecular modeling showing 32 anesthetic binding sites per tubulin, with at least 1 percent (10 million) of the billion tubulins per brain neuron binding an anesthetic molecule at clinical concentration (1 ‘MAC’). Two particular anesthetic binding regions may destabilize MTs, one inactivating tubulin C-termini tails (which otherwise knit together neighboring tubulins). The other weakens side-to-side tubulin couplings, the critical link in MT lattices, but only at high anesthetic concentrations, or perhaps with other MT destabilizing factors (low temperature, low zinc, high calcium, acidosis).

Travis Craddock PhD, lead author on the study said: “The good news is that therapies aimed at microtubule stabilization may help in both Alzheimer’s and post-anesthetic dementias. Clinical trials are underway, or planned, for microtubule stabilizers Epothilone D, NAPVSIPQ, and the zinc ionophore PBT2, as well as brain ultrasound, shown in vitro to excite MT resonances and promote polymerization. However it’s done, ‘tightening the tubules’ may best treat dementia.”

Source: Science Daily

June 27th, 2012

Long-term aim is to develop new treatments to block the spread of damaged proteins in the brain.

Van Andel Institute announces that researchers at Lund University in Sweden have published a study detailing how Parkinson’s disease spreads through the brain. Experiments in rat models uncover a process previously used to explain mad cow disease, in which misfolded proteins travel from sick to healthy cells. This model has never before been identified so clearly in a living organism, and the breakthrough brings researchers one step closer to a disease-modifying drug for Parkinson’s.

“Parkinson’s is the second most common neurodegenerative disorder after Alzheimer’s disease,” said Patrik Brundin M.D., Ph.D., Jay Van Andel Endowed Chair in Parkinson’s Research at Van Andel Research Institute (VARI), Head of the Neuronal Survival Unit at Lund University and senior author of the study. “A major unmet medical need is a therapy that slows disease progression. We aim to better understand how Parkinson’s pathology progresses and thereby uncover novel molecular targets for disease-modifying treatments.”

Previous research demonstrates that a misfolded protein known as alpha-synuclein protein gradually appears in healthy young neurons transplanted to the brains of Parkinson’s patients. This discovery gave rise to the group’s hypothesis of cell-to-cell protein transfer, which has since been demonstrated in laboratory experiments.

In the current study, published this week in the Public Library of Science (PLoS ONE), researchers for the first time were able to follow events in the recipient cell as it accepts the diseased protein by allowing it to pass its outer cell membrane. The experiments also show how the transferred proteins attract proteins in the host cell leading to abnormal folding or “clumping” inside the cells.

Coronal section at the level of the gyrus diagonalis of a rat transplanted with VM tissue six weeks after AAV2/6-huαsyn injection and sacrificed four weeks after grafting. The immunohistochemical analysis with antibodies directed against huαsyn shows the overexpression of this protein in the axon terminals of the right striatum. The center of the bilateral grafts is marked with an asterisk. On the right, the graft is clearly located in the area devoid of signal. The image and description were adapted from a PLoS ONE research paper image credited at the end of this article. doi:10.1371/journal.pone.0039465.g001

“This is a cellular process likely to lead to the disease process as Parkinson’s progresses, and it spreads to an increasing number of brain regions as the patient gets sicker,” said Elodie Angot, Ph.D., of Lund University’s Neuronal Survival Unit, and lead co-author of the study.

“In our experiments, we show a core of unhealthy human alpha-synuclein protein surrounded by alpha-synuclein produced by the rat itself. This indicates that this misfolded protein not only moves between cells but also acts as a “seed” attracting proteins produced by the rat’s brain cells,” said Jennifer Steiner, Ph.D., of Lund University and Van Andel Institute’s Center for Neurodegenerative Science, the study’s other lead author.

These findings are consistent with results from previous laboratory cell models and for the first time extend this observation into a living organism. However, it remains unclear exactly how alpha-synuclein gains access from the extracellular space to the cytoplasm of cells to act as a template for naturally occurring alpha-synuclein, causing the naturally-occurring protein to, in turn, misfold. Further studies are needed to clarify this important step in the process.

The discovery does not reveal the root of Parkinson’s disease, but in conjunction with disease models developed by Lund University researchers and others, could enable scientists to develop new drug targets aimed at mitigating or slowing the effects of the disease, which currently strikes more than 1% of people over the age of 65.

Source: Neuroscience News

ScienceDaily (June 27, 2012) — An international team including scientists from the University of Saskatchewan-Saskatoon Health Region and University of British Columbia, with the help of Saskatchewan Mennonite families, has identified an abnormal gene which leads to Parkinson’s disease.

"This discovery paves the way for further research to determine the nature of brain abnormalities which this gene defect produces," says Dr. Ali Rajput, a world expert in Parkinson’s disease who has been studying the disease for 45 years and working with the main family in the study since 1983.

"It also promises to help us find ways to detect Parkinson’s disease early, and to develop drugs which will one day halt the progression of the disease."

The abnormal gene is a mutated version of a gene called DNAJC13, identified by UBC medical genetics professor Matthew Farrer, who led the study.

Thirteen of 57 members of one extended Saskatchewan family in the study had been previously diagnosed with Parkinson’s disease. Three other single cases from Saskatchewan and one family from British Columbia were also found to have the same mutation. All were of Mennonite background, a Christian group who share Dutch-German-Russian ancestry.

The findings were presented last week to the more than 5,000 delegates at the 16th International Congress of Parkinson’s Disease and Movement Disorders in Dublin, Ireland.

Rajput and his son, fellow neurologist and researcher Alex Rajput, are long-time collaborators of Farrer. The research drew on the Rajputs’ work over the past four decades. The research team also includes scientists from McGill University, the Mayo Clinic in Florida, and St. Olav’s Hospital in Norway.

A key contribution is the Rajputs’ collection of more than 500 brains and nearly 2,200 blood samples from Parkinson’s patients. Farrer explains that confirmation of the gene’s linkage with Parkinson’s disease required DNA samples from thousands of patients with the disease and healthy individuals. He adds that the contributions of the Saskatchewan Mennonite family, who have asked to remain anonymous, were critical.

"A breakthrough like this would not be possible without their involvement and support. They gave up considerable time, contributed clinical information, donated blood samples, participated in PET imaging studies and — on more than one occasion following the death of a family member — donated brain samples," says Farrer, who holds the Canada Excellence Research Chair in Neurogenetics and Translational Neuroscience.

"The whole-hearted and unselfish commitment of this family is remarkable," Rajput says. "They went out of their way in every conceivable manner to help solve this mystery. We, on behalf of all the Parkinson’s disease patients in this province, Canada, and around the world, are grateful to them for making this discovery possible."

In a Parkinson’s patient, cells in an area of the brain called the substantia nigra (black substance) die and there are abnormal, round clumps of protein known as Lewy bodies inside the brain cells. Examination of the brains from the Mennonite family revealed the same Lewy body Parkinson’s disease as seen in other patients.

Parkinson’s disease is a progressive condition that causes symptoms such as tremors, slowness of movement, stiffness, and mental impairment. In most cases, symptoms appear after age 40. It is estimated that about one million people in North America and more than four million people worldwide are affected by the disease.

Source: Science Daily

June 27th, 2012

RTC 13 effectively counteracts ‘nonsense’ mutation that causes disorder.

Scientists at UCLA have identified a new compound that could treat certain types of genetic disorders in muscles. It is a big first step in what they hope will lead to human clinical trials for Duchenne muscular dystrophy.

Duchenne muscular dystrophy, or DMD, is a degenerative muscle disease that affects boys almost exclusively. It involves the progressive degeneration of voluntary and cardiac muscles, severely limiting the life span of sufferers.

In a new study, senior author Carmen Bertoni, an assistant professor in the UCLA Department of Neurology, first author Refik Kayali, a postgraduate fellow in Bertoni’s lab, and their colleagues demonstrate the efficacy of a new compound known as RTC13, which suppresses so-called “nonsense” mutations in a mouse model of DMD.

The findings appear in the current online edition of the journal Human Molecular Genetics.

“We are excited about these new findings because they represent a major step toward the development of a drug that could potentially treat this devastating disease in humans,” Bertoni said. “We knew that the compounds were effective in cells isolated from the mouse model for DMD, but we did not know how they would behave when administered in a living organism.”

Histopathology of gastrocnemius muscle from patient who died of pseudohypertrophic muscular dystrophy, Duchenne type. Cross section of muscle shows extensive replacement of muscle fibers by adipose cells.

Nonsense mutations are generally caused by a single change in DNA that disrupts the normal cascade of events that changes a gene into messenger RNA, then into a protein. The result is a non-functioning protein. Approximately 13 percent of genetic defects known to cause diseases are due to such mutations. In the case of DMD, the “missing” protein is called dystrophin.

For the study, Bertoni and Kayali collaborated with the laboratory of Dr. Richard Gatti, a professor of pathology and laboratory medicine and of human genetics at UCLA. Working with the UCLA Molecular Shared Screening Resource facility at the campus’s California NanoSystems Institute, the Gatti lab screened some 35,000 small molecules in the search for new compounds that could ignore nonsense mutations. Two were identified as promising candidates: RTC13 and RTC14.

The Bertoni lab tested RTC13 and RTC14 in a mouse model of DMD carrying a nonsense mutation in the dystrophin gene. While RTC14 was not found to be effective, RTC13 was able to restore significant amounts of dystrophin protein, making the compound a promising drug candidate for DMD. When RTC13 was administered to mice for five weeks, the investigators found that the compound partially restored full-length dystrophin, which resulted in a significant improvement in muscle strength. The loss of muscle strength is a hallmark of DMD.

The researchers also compared the level of dystrophin achieved to the levels seen with another experimental compound, PTC124, which has proved disappointing in clinical trials; RTC13 was found to be more effective in promoting dystrophin expression. Just as important, Bertoni noted, the study found that RTC13 was well tolerated in animals, which suggests it may also be safe to use in humans.

The next step in the research is to test whether an oral formulation of the compound would be effective in achieving therapeutically relevant amounts of dystrophin protein. If so, planning can then begin for clinical testing in patients and for expanding these studies to other diseases that may benefit from this new drug.

Source: Neuroscience News

June 27th, 2012

Weill Cornell researchers develop novel antibody vaccine that blocks addictive nicotine chemicals from reaching the brain.

Researchers at Weill Cornell Medical College have developed and successfully tested in mice an innovative vaccine to treat nicotine addiction.

In the journal Science Translational Medicine, the scientists describe how a single dose of their novel vaccine protects mice, over their lifetime, against nicotine addiction. The vaccine is designed to use the animal’s liver as a factory to continuously produce antibodies that gobble up nicotine the moment it enters the bloodstream, preventing the chemical from reaching the brain and even the heart.

“As far as we can see, the best way to treat chronic nicotine addiction from smoking is to have these Pacman-like antibodies on patrol, clearing the blood as needed before nicotine can have any biological effect,” says the study’s lead investigator, Dr. Ronald G. Crystal , chairman and professor of Genetic Medicine at Weill Cornell Medical College.

“Our vaccine allows the body to make its own monoclonal antibodies against nicotine, and in that way, develop a workable immunity,” Dr. Crystal says.

The new vaccine has been tested in mice and could one day help people to quit smoking cigarettes, should they choose. Much testing remains until the vaccine can be tested in humans. Image is in the public domain.

Previously tested nicotine vaccines have failed in clinical trials because they all directly deliver nicotine antibodies, which only last a few weeks and require repeated, expensive injections, Dr. Crystal says. Plus, this kind of impractical, passive vaccine has had inconsistent results, perhaps because the dose needed may be different for each person, especially if they start smoking again, he adds.

“While we have only tested mice to date, we are very hopeful that this kind of vaccine strategy can finally help the millions of smokers who have tried to stop, exhausting all the methods on the market today, but find their nicotine addiction to be strong enough to overcome these current approaches,” he says. Studies show that between 70 and 80 percent of smokers who try to quit light up again within six months, Dr. Crystal adds.

About 20 percent of adult Americans smoke, and while it is the 4,000 chemicals within the burning cigarette that causes the health problems associated with smoking — diseases that lead to one out of every five deaths in the U.S. — it is the nicotine within the tobacco that keeps the smoker hooked.

A new kind of vaccine

There are, in general, two kinds of vaccines. One is an active vaccine, like those used to protect humans against polio, the mumps, and so on. This kind of vaccine presents a bit of the foreign substance (a piece of virus, for example) to the immune system, which “sees” it and activates a lifetime immune response against the intruder. Since nicotine is a small molecule, it is not recognized by the immune system and cannot be built into an active vaccine.

The second type of vaccine is a passive vaccine, which delivers readymade antibodies to elicit an immune response. For example, the delivery of monoclonal (identically produced) antibodies that bind on to growth factor proteins on breast cancer cells shut down their activity.

The Weill Cornell research team developed a new, third kind — a genetic vaccine — that they initially tested in mice to treat certain eye diseases and tumor types. The team’s new nicotine vaccine is based on this model.

The researchers took the genetic sequence of an engineered nicotine antibody, created by co-author Dr. Jim D. Janda, of The Scripps Research Institute, and put it into an adeno-associated virus (AAV), a virus engineered to not be harmful. They also included information that directed the vaccine to go to hepatocytes, which are liver cells. The antibody’s genetic sequence then inserts itself into the nucleus of hepatocytes, and these cells start to churn out a steady stream of the antibodies, along with all the other molecules they make.

In mice studies, the vaccine produced high levels of the antibody continuously, which the researchers measured in the blood. They also discovered that little of the nicotine they administered to these mice reached the brain. Researchers tested activity of the experimental mice, treated with both a vaccine and nicotine, and saw that it was not altered; infrared beams in the animals’ cages showed they were just as active as before the vaccine was delivered. In contrast, mice that received nicotine and not treated with the vaccine basically “chilled out” — they relaxed and their blood pressure and heart activity were lowered — signs that the nicotine had reached the brain and cardiovascular system.

The researchers are preparing to test the novel nicotine vaccine in rats and then in primates — steps needed before it can be tested ultimately in humans.

Dr. Crystal says that, if successful, such a vaccine would best be used in smokers who are committed to quitting. “They will know if they start smoking again, they will receive no pleasure from it due to the nicotine vaccine, and that can help them kick the habit,” he says.

He adds that it might be possible, given the complete safety of the vaccine, to use it to preempt nicotine addiction in individuals who have never smoked, in the same way that vaccines are used now to prevent a number of disease-producing infections. “Just as parents decide to give their children an HPV vaccine, they might decide to use a nicotine vaccine. But that is only theoretically an option at this point,” Dr. Crystal says. “We would of course have to weight benefit versus risk, and it would take years of studies to establish such a threshold.”

“Smoking affects a huge number of people worldwide, and there are many people who would like to quit, but need effective help,” he says. “This novel vaccine may offer a much-needed solution.”

Source: Neuroscience News

June 27, 2012

Smoking, head injury, pesticide exposure, farming and less education may be risk factors for a rare sleep disorder that causes people to kick or punch during sleep, according to a study published in the June 27, 2012, online issue of Neurology, the medical journal of the American Academy of Neurology.

People with the disorder, called REM sleep behavior disorder, do not have the normal lack of muscle tone that occurs during rapid eye movement (REM) sleep, causing them to act out their dreams. The movements can sometimes be violent, causing injury to the person or their bed partner. The disorder is estimated to occur in 0.5 percent of adults.

"Until now, we didn’t know much about the risk factors for this disorder, except that it was more common in men and in older people," said study author Ronald B. Postuma, MD, MSc, with the Research Institute of the McGill University Health Centre (MUHC) in Montreal and a member of the American Academy of Neurology. "Because it is a rare disorder, it was difficult to gather information about enough patients for a full study. For this study, we worked with 13 institutions in 10 countries to get a full picture of the disorder."

The disorder can also be a precursor to neurodegenerative diseases such as Parkinson’s disease and a type of dementia. Studies have shown that more than 50 percent of people with REM sleep behavior disorder go on to develop a neurodegenerative disorder years or even decades later.

"Due to this connection, we wanted to investigate whether the risk factors for REM sleep behavior disorder were similar to those for Parkinson’s disease or dementia," Postuma said.

The results were mixed. While smoking has found to be a protective factor for Parkinson’s disease, people who smoked were found to be more likely to develop REM sleep behavior disorder. Pesticide use, on the other hand, is a risk factor for both disorders. Studies have shown that people who drink coffee are less likely to develop Parkinson’s, but this study found no relationship between coffee drinking and REM sleep behavior disorder.

For the study, 347 people with REM sleep behavior disorder were compared to 347 people who did not have the disorder. Of those, 218 had other sleep disorders and 129 had no sleep disorders.

Those with REM sleep behavior disorder were 43 percent more likely to be smokers, with 64 percent of those with the disorder having ever smoked, compared to 56 percent of those without the disorder. They were 59 percent more likely to have had a previous head injury with loss of consciousness, 67 percent more likely to have worked as farmers, and more than twice as likely to have been exposed to pesticides through work. Those with the disorder also had fewer years of education, with an average of 11.1 years, compared to 12.7 years for those without the disorder.

More information: To learn more about sleep disorders, visit http://www.aan.com/patients

Provided by American Academy of Neurology

Source: medicalxpress.com

June 27, 2012 by Bob Yirka

(Medical Xpress) — Research teams from the US and Korea have together been studying depression and other mood disorders and have found that chronic stress can block a gene whose job it is to maintain healthy neuron connections in the brain, which in turn can lead to mental ailments. In lab experiments they have found that rats show lowered levels of neuritin gene activity when driven to depression, and that rats with depression tended to do better when given treatment that boosted neuritin activity, suggesting that another means of treating people with mood disorders might be on the horizon. The team has published a paper describing their experiments and results in the Proceedings of the National Academy of Sciences.

Prior research has shown that people who suffer from chronic depression tend to lose plasticity, or the ability to organize new information in their brains, specifically in the hippocampus, leading to a degree of atrophy, a condition that makes it difficult for such people to recover from their disorder even when given drugs to help treat the symptoms. Until now however, most drugs that are used to treat mood disorders work by blocking the re-absorption of the brain chemical serotonin. In this new research, the team looked at the role of neuritin gene activity instead.

In lab experiments they first caused rats to become depressed by exposing them to a constantly stressful environment, e.g. putting them alone in a sterile environment, limiting food and alternating their night/day cycle. After about three weeks the rats became lethargic and unresponsive to normal stimuli. Once that was done, they tested them for the degree of neuritin gene activity, and found that such levels had dropped in all of them. They then treated some of the rates with standard mood stabilizers which helped reduced symptoms as it has in previous research. But then, they treated some of the other rats by infecting them with a virus that causes an increase in neuritin gene activity and found doing so helped the rats just as much as standard therapies and also served to protect their brains from atrophy.

In another experiment the team forced lowered neuritin gene activity in a group of rats but didn’t subject them to stress and found the rats became just as depressed as had those in the first experiment.

The team notes that while their results look very promising on paper, assuming the same results would occur with people is premature as there are differences in biology. Their results do however support the notion that stress itself contributes to mood disorders, which is information people can use to help them live more mentally healthy lives right now.

More information: Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress, PNAS, Published online before print June 25, 2012, doi: 10.1073/pnas.1201191109

Source: medicalxpress.com

June 27th, 2012

Researchers from the Huck Institutes’ Center for Cellular Dynamics, led by Center director Melissa Rolls, have found that a neuroprotective pathway initiated in response to injured or stressed neural axons serves to stabilize and protect the nerve cell against further degeneration.

Neurons, or nerve cells, typically have a single axon that transmits signals to other neurons or to output cells such as muscle tissue, and as these axons extend for long distances within the cell, they are thus at risk for injury.

Furthermore, if an axon is damaged, its parent neuron can no longer function; and since many animals develop only one set of neurons, those neurons will mount major responses to axon injury.

“Neurons are quite remarkable cells,” says Dr. Rolls. “Most of them need to survive and function for your entire lifetime. Maybe then it shouldn’t be a surprise that they do not give up easily when damaged or stressed, but it is amazing to be able to watch them fight back and stabilize themselves.”

Neurons expressing a toxic form of spinocerebellar ataxia type 3 (SCA3) with protective pathway enabled (left) and blocked (right). Image adapted from Penn State press release image with credit to Melissa Rolls. Click for larger view and original image from Penn State.

Dissecting Drosophila

Dr. Rolls and her team set out to understand these cellular responses to axon injury by observing the effects of severing fruit fly axons with a laser.

What they found was that the neurons responded to the injury by increasing production of microtubules — cytoskeletal components responsible for maintaining cell structure and providing platforms for intracellular transport — in order to stabilize the neural dendrites, which are the branched structures responsible for transmitting signals to the nerve cell body.

In addition to acute injury response, the team also investigated neurons’ response to long-term axon stress — and found similar results.

Accumulation of misfolded proteins or protein aggregates — responsible for neurodegenerative diseases such as Huntington’s disease and spinocerebellar ataxia — induced the same type of cytoskeletal changes as acute axon injury.

Dr. Rolls elaborates: “The assays that we use are all in vivo, so we can literally watch what the neurons do in different scenarios, including cutting of their axon. Being able to observe the cellular responses gave us some ideas we would not have come up with otherwise. For example, it is not intuitive that expressing a protein that causes degeneration would trigger the cell to turn on a pathway that delays degeneration.”

The neuroprotective pathway

The video below shows the difference in microtubule dynamics between cells expressing a non-toxic form of the huntingtin protein (left) and cells expressing a disease-causing form (right).

[Video: Axon injury and stress trigger a microtubule-based neuroprotective pathway]
Credit: Melissa Rolls, Director, Center for Cellular Dynamics

Conclusions and implications

Based on their observations, the authors suggest that this pathway represents an endogenous neuroprotective response to axon stress — and could potentially be developed into a diagnostic tool for the detection of early stages of neurodegenerative disease, or even utilized in novel therapies for such illnesses.

“We don’t yet know if all types of neurodegenerative disease trigger this type of stabilization pathway; but if there are some diseases in which it is off, then it may be beneficial to try to turn it on to help the neurons resist degeneration,” says Dr. Rolls.

The results of the study have been published in Proceedings of the National Academy of Sciences.

Source: Neuroscience News

ScienceDaily (June 27, 2012) — Scientists at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg have gained important insights for stem cell research which are also applicable to human tumours and could lead to the development of new treatments. As Rolf Kemler’s research group discovered, a molecular link exists between the telomerase that determines the length of the telomeres and a signalling pathway known as the Wnt/β-signalling pathway.

Telomeres are the end caps of chromosomes that play a very important role in the stability of the genome. Telomeres in stem cells are long and become shorter during differentiation or with age, but lengthen again in tumour cells.

The Wnt/β-catenin signalling pathway controls numerous processes in embryonic development, such as the formation of the body axis and of organ primordia, and is particularly active in embryonic and adult stem cells. The β-catenin protein plays a key role in this signalling pathway. The incorrect regulation or mutation of β-catenin leads to the development of tumours.

Rolf Kemler’s research group has now shown that β-catenin regulates the telomerase gene directly, and has explained the molecular mechanism at work here. Embryonic stem cells with mutated β-catenin generate more telomerase and have extended telomeres, while cells without β-catenin have low levels of telomerase and have shortened telomeres.

This regulation mechanism can also be found in human cancer cells. These discoveries could lead to the development of a new approach to the treatment of human tumours.

Source: Science Daily

ScienceDaily (June 27, 2012) — A new study shows significant differences in brain development in high-risk infants who develop autism starting as early as age 6 months. The findings published in the American Journal of Psychiatry reveal that this abnormal brain development may be detected before the appearance of autism symptoms in an infant’s first year of life. Autism is typically diagnosed around the age of 2 or 3.

The study offers new clues for early diagnosis, which is key, as research suggests that the symptoms of autism — problems with communication, social interaction and behavior — can improve with early intervention. “For the first time, we have an encouraging finding that enables the possibility of developing autism risk biomarkers prior to the appearance of symptoms, and in advance of our current ability to diagnose autism,” says co-investigator Dr. Alan Evans at the Montreal Neurological Institute and Hospital — the Neuro, McGill University, which is the Data Coordinating Centre for the study.

"Infancy is a time when the brain is being organized and connections are developing rapidly," says Dr. Evans. "Our international research team was able to detect differences in the wiring by six months of age in those children who went on to develop autism. The difference between high-risk infants that developed autism and those that did not was specifically in white matter tract development — fibre pathways that connect brain regions." The study followed 92 infants from 6 months to age 2. All were considered at high-risk for autism, as they had older siblings with the developmental disorder. Each infant had a special type of MRI scan, known as diffusion tensor imaging, at 6 months and a behavioral assessment at 24 months. The majority also had additional scans at either or both 12 and 24 months.

At 24 months, 30% of infants in the study were diagnosed with autism. White matter tract development for 12 of the 15 tracts examined differed significantly between the infants that developed autism and those who did not. Researchers evaluated fractional anisotropy (FA), a measure of white matter organization based on the movement of water through tissue. Differences in FA values were greatest at 6 and 24 months. Early in the study, infants who developed autism showed elevated FA values along these tracts, which decreased over time, so that by 24 months autistic infants had lower FA values than infants without autism.

The study characterizes the dynamic age-related brain and behavior changes underlying autism — vital for developing tools to aid autistic children and their families. This is the latest finding from the on-going Infant Brain Imaging Study (IBIS), which is funded by the National Institutes of Health (NIH) and brings together the expertise of a network of researchers from institutes across North America. The IBIS study is headquartered at the University of North Carolina, and The Neuro is the Data Coordinating Centre where all IBIS data is centralized.

Source: Science Daily

June 26, 2012

Researchers at the University of Michigan have found that the Apple iPad 2 can interfere with settings of magnetically programmable shunt devices, which are often used to treat children with hydrocephalus. The iPad 2 contains magnets that can change valve settings in the shunt if the tablet computer is held too close to the valve (within 2 inches). Such a change may result in shunt malfunction until the problem is recognized and the valve adjusted to the proper setting. Patients and their caregivers should monitor use of the tablet computer to ensure that no change is made to the valve settings. The results of this study can be found in the article “Programmable shunt valve affected by exposure to a tablet computer. Laboratory investigation,” by Strahle and colleagues, published in the August 2012 issue of the Journal of Neurosurgery: Pediatrics and available online today.

The researchers first thought of performing this study because a tablet computer seemed to affect a programmable shunt in one of their patients, a 4-month-old girl with hydrocephalus. Three weeks after the baby had received the shunt, she was examined for shunt malfunction due to a changed setting in the magnetically programmable valve that regulates the flow of cerebrospinal fluid. The baby’s mother stated that she had held an iPad 2 while holding the infant. Programmable shunt valve settings can be altered by exposure to magnetic fields. Indeed, specialized magnets are used by physicians to adjust the settings on these valves. Since in this case no other environmental factor could be identified that would have led to a shift in the valve settings, the authors decided to test whether the iPad 2 might be implicated because, unlike the initial iPad, the iPad 2 contains several magnets and is often used with an Apple Smart Cover, which contains additional magnets.

The researchers tested 10 programmable shunt valves with a variety of settings. They exposed the valves to an iPad 2 with and without the Smart Cover at different distances: less than 1 centimeter (cm), 1 to 2.5 cm, 2.5 to 5 cm, 5 to 10 cm, and greater than 10 cm. Each exposure lasted 10 seconds. Overall, the valves were tested 100 times for each of the five distances during exposures to the iPad 2 with the Smart Cover closed and 30 times for distances less than 1 cm for the tablet computer without the cover.

After exposure of the programmable valves to the iPad 2 and Smart Cover at distances between 0 and 1 cm, the researchers found that the settings had changed in 58 percent of the valves. After exposure at distances between 1 and 2.5 cm the settings had changed in 5 percent of valves, and after exposure at distances between 2.5 and 5 cm the settings had changed in only 1 percent of valves. No changes in valve settings were identified after exposures at higher distances.

After exposure of programmable valves to the iPad 2 without a cover, which was only tested at distances between 0 and 1 cm, the researchers found that the settings had changed in 67 percent of the valves.

Although no change in setting was found past a distance of 5 cm (2 inches), the authors caution that patients and caregivers should be made aware of the potential for a change in the settings of a magnetically programmable shunt valve if an iPad 2 is placed very near. This is not to say that the iPad 2 cannot be safely used in the vicinity of patients with programmable shunts. A variety of magnets can be found in households today, and the authors state that the magnetic field strength of the iPad 2 lies within the range of these everyday magnets. Therefore, patients and caregivers should regard precautions surrounding the use of the iPad 2 to be the same as those taken with other household magnets. Cormac Maher, M.D., a pediatric neurosurgeon and lead author of the report, said that he hopes to raise awareness of this potential interaction through publication of this study.

Provided by Journal of Neurosurgery Publishing Group

Source: medicalxpress.com

ScienceDaily (June 26, 2012) — In the brains of humans and non-human primates, over 100 billion nerve cells build up complicated neural circuits and produce higher brain functions. When an attempt is made to perform gene therapy for neurological diseases like Parkinson’s disease, it is necessary to specify a responsible neural circuit out of many complicated circuits. Until now, however, it was difficult to introduce a target gene into this particular circuit selectively.

The collaborative research group consisting of Professor Masahiko Takada from Primate Research Institute, Kyoto University, Professor Atsushi Nambu from National Institute for Physiological Sciences, National Institutes of Natural Sciences, and Professor Kazuto KOBAYASHI from Fukushima Medical University School of Medicine have now developed a gene transfer technique that can “eliminate”a specific neural circuit in non-human primates for the first time.

They applied this technique to the basal ganglia, the brain region that is affected in movement disorders such as Parkinson’s disease, and successfully eliminated a particular circuit selectively to elucidate its functional role. This technique can be applied to gene therapy for various neurological diseases in humans. This research achievement was supported by the Strategic Research Program of Brain Sciences by MEXT of Japan.

The research group developed a special viral vector, NeuRet-IL-2R alpha-GFP viral vector, expressing human interleukin type 2 alpha receptor, which the cell death inducer immunotoxin binds. Nerve cells transfected with this viral vector cause cell death by immunotoxin. First, the research group injected the viral vector into the subthalamic nucleus that is a component of the basal ganglia. Then, they injected immunotoxin into the motor cortex, an area of the cerebral cortex that controls movement, and succeed in selective elimination of the “hyperdirect pathway” that is one of the major circuits connecting the motor cortex to the basal ganglia. As a result, they have discovered that neuronal excitation observed at the early stage occurs through this hyperdirect pathway when motor information derived from the cortex enters the basal ganglia.

Professors Takada and Nambu expect that this gene transfer technique enables us to elucidate higher brain functions in primates and to develop primate models of various psychiatric/neurological disorders and their potential treatments including gene therapy. They think that this should provide novel advances in the field of neuroscience research that originate from Japan.

Source: Science Daily

ScienceDaily (June 26, 2012) — Magnetic fields generated by microscopic devices implanted into the brain may be able to modulate brain-cell activity and reduce symptoms of several neurological disorders. Micromagnetic stimulation appears to generate the kind of neural activity currently elicited with electrical impulses for deep brain stimulation (DBS) — a therapy that can reduce symptoms of Parkinson’s disease, other movement disorders, multiple sclerosis and chronic pain — and should avoid several common problems associated with DBS, report Massachusetts General Hospital investigators.

"We have shown that fields generated by magnetic coils small enough to be implanted into the central nervous system can be used to modulate the activity of neurons, potentially leading to a new generation of neural prosthetics that are safer and possibly more effective than conventional electrical stimulation devices," says Giorgio Bonmassar, PhD, of the Martinos Center for Biomedical Imaging at MGH, co-lead author of the report in the online journal Nature Communications.

DBS involves implantation of small electrodes called leads into structures deep within the brain. The leads, connected to a battery-operated power source implanted into the abdomen, generate electrical signals that modulate neural activity at sites that vary depending on the condition being treated. DBS has successfully alleviated symptoms in patients not helped by other therapies, but it does have limitations. Magnetic resonance imaging (MRI) can cause metallic DBS implants to heat up and damage adjacent brain tissue, which limits the use of MRI in these patients. In addition, the presence of DBS implants typically elicits an immune system response, leading to scarring around the implant that can block the electrical signal.

Magnetic stimulation has been used to diagnose and treat neurological disorders for two decades, but until now it has required the use of large hand-held coils that generate fields from outside the skull, limiting the brain structures that can be stimulated and the accuracy with which a signal can be delivered. The current study was designed to investigate the potential of much smaller magnetic coils to generate the kind of neural activity produced by DBS, exploring a concept first developed by Bonmassar. The investigators first developed a computational simulation that verified that magnetic coils 1 millimeter long and .5 mm in diameter would generate magnetic and electrical fields that should stimulate neuronal activity.

The research team then tested whether a commercially available coil of that size, coated with a plastic material, would activate neurons in retinal tissue. Positioned right above retinal tissue and either parallel or perpendicular to the tissue surface, the coil generated fields that successfully elicited neuronal signals in retinal cells. How the coil was positioned relative to the retinal surface produced significant differences in the physiologic responses. When the coil was oriented parallel to the retina, the induced field appeared to activate retinal bipolar cells, which transmit signals from the light-sensing photoreceptors to retinal ganglion cells. A coil oriented perpendicular to the retina produced responses indicative of ganglion cell activation.

"These differences suggest that, by modifying the geometry of the coil, we may be able to selectively target populations of neurons and minimize the effects on non-targeted cells," says Shelley Fried, PhD, of the MGH Department of Neurosurgery, corresponding author of the Nature Communications report. “By sizing and orienting the coil appropriately to any given population of central nervous system neurons, we should be able to either activate or avoid activation of that population.

"This study provides a proof of concept that small coils can activate neurons, and much work still needs to be done," he adds. "We need to explore how to optimize coil properties and then evaluate the devices in animal models. We also hope to explore the use of these coils in non-DBS applications, including cardiovascular procedures such as heart muscle pacing." Fried is an instructor in Surgery and Bonmassar an assistant professor of Radiology at Harvard Medical School.

Source: Science Daily

ScienceDaily (June 26, 2012) — Scientists from the University of Barcelona (UB) in collaboration with a multidisciplinary team from the Spanish National Research Council (CSIC) has discovered a mechanism that prevents alterations in neurogenesis, the process of neuronal formation, during the development of the nervous system in vertebrates. The study, published in the journal Development, relates these distortions to the natural presence of a molecule that inhibits the neuronal formation at the regions adjacent to the tissue suitable for neurogenesis.

Left: altered neurogenic wavefront in the absence of Delta. Right: normal neurogenic wavefront. (Credit: Image courtesy of Universidad de Barcelona)

Through a theoretical and computational analysis of the retina, scientists have found that lateral inhibition, a process that regulates the generation of neurons in the central nervous system, undergoes alterations at the neurogenic wavefront (i.e. the edge between the regions that generate neurons and the adjacent areas, where neurogenesis has not yet begun).

"The study shows that the absence of the Delta molecule at the adjacent regions reduces the robustness of the neurogenic process, often resulting in an increased production of neurons or in the presence of morphological alterations of the wavefront. These alterations could be catastrophic for the proper development of the nervous system," explains José María Frade, researcher from the CSIC, at the Cajal Institute.

Lateral inhibition during embryonic development aims to control the amount of neurons that are formed. It consists in cells that inhibit other neighbouring cells, promoting neuronal differentiation. “Neuronal precursor cells expressing high levels of Delta induce inhibitory signals in neighbouring cells. These inhibitory signals reduce the capacity of these cells to express Delta itself and, in turn, facilitate the differentiation of the high Delta-expressing precursors. Thus, the massive generation of neurons is avoided and the orderly production of different types of neurons necessary for brain function is facilitated,” explains researcher from the CSIC Saúl Ares, who works at the Spanish National Biotechnology Centre.

Previous theoretical studies suggested that the lateral inhibition process can be altered at the neurogenic edges. “However, the importance of this inhibition process had not been appropriately acknowledged. Our study demonstrates the relevance of Delta expression ahead of the neurogenic wavefront, provides predictions and explains developmental alterations resulting from the absence of Delta. It also represents a breakthrough in the theoretical field because it formulates a front propagation mechanism based on self-regulatory mechanisms,” points out Marta Ibañes, researcher from the UB.

According to researchers, this study provides a new concept that will attract the attention of neurobiologists who work both in the development of the nervous system and in several pathologies derived from neuronal development.

Source: Science Daily

26 June 12 | By Liat Clark

A UK mathematician has made a public appeal for people to phone a dedicated number so data can be gathered to hone a tool that can diagnose Parkinson’s disease by analysing voice patterns.

Image: Shutterstock

Max Little, a research fellow at the Massachusetts Institute of Technology, made the announcement during the opening of the TEDGlobal conference in Edinburgh, 25 June. While studying at Oxford University, Little developed an algorithm that identifies the unique characteristics present in the voice of a Parkinson’s Disease sufferer. He setup the Parkinson’s Voice Initiative in order to improve upon the machine learning system — the algorithm is built to adapt when new information is introduced and, by widening the pool (it’s hoped, with 10,000 phone calls form the public), it should become a more accurate diagnosis tool, able to identify specific symptoms amid numerous variants of speech.

"This raises a very interesting possibility," Little says in a promotional video. "If we could use the entire existing telephone network then we could scale up the screening of Parkinson’s disease to the entire population, and do it at very minimal cost."

Other than the UK, there are phone numbers on the Parkinson’s Voice Initiative website for people in the US, Brazil, Mexico, Spain, Argentina and Canada. Parkinson’s sufferers and non-sufferers are both encouraged to call in anonymously. The calls should only last around three minutes. By getting non-sufferers to call in, the system can learn to weed out and discard unnecessary voice patterns, such as those brought on by a cold or heavy smoking.

Around 70-90 percent of sufferers report instances of vocal impairment following the onset of the disease. Little’s proposal therefore presents opportunities for widespread remote diagnosis.

He first presented the diagnosis tool’s successful testing in a paper published earlier this year in the IEEE Transactions journal. Little and co-author Athanasios Tsanas explained how 43 candidates were asked to hold one sound frequency for as long as possible. They collected 263 data samples in this way, and from this extracted 132 different vocal impairments. Using only ten of these recorded impairments, the algorithm could diagnose Parkinson’s speech markers accurately 99 percent of the time. The system is trained to identify the anomalies in the speech.

By collating more data in the future, the range of these vocal features could be widened, lessening the margin of error even more.

The paper suggests that in the future, data could be collected using Intel’s At-Home Testing Device, a telemonitoring system. It would then be sent to a clinic where the algorithm processes it and maps out the speech, identifying markers on the Unified Parkinson’s Disease Rating Scale (UPDRS) so that the severity of the illness is known. In this way, the system could not only be used to diagnose, but to monitor the progression of the disease.

Voice recognition could be a cheap and efficient alternative to having patients’ head to their GP for a twenty-minute diagnosis session. There is currently no simple diagnosis tool — no blood test that can identify Parkinson’s — and vocal tremors, breathiness and reduced speech volume are some of the first symptoms recorded in nearly all patients. These can be very subtle at the start, however, and systems such as Little’s could conceivably pick up the slightest abnormal intonation.

Parkinson’s Disease is the second most common neurodegenerative disorder after Alzheimer’s and, since it can only be treated with drugs or surgery and cannot be cured, early diagnosis can massively effect an individual’s quality of life.

Source: wired.co.uk

ScienceDaily (June 26, 2012) — UCLA researchers discovered that a diet enriched with a popular omega-3 fatty acid and an ingredient in curry spice preserved walking ability in rats with spinal-cord injury. Published June 26 in the Journal of Neurosurgery: Spine, the findings suggest that these dietary supplements help repair nerve cells and maintain neurological function after degenerative damage to the neck.

Turmeric. (Credit: © Elzbieta Sekowska / Fotolia)

"Normal aging often narrows the spinal canal, putting pressure on the spinal cord and injuring tissue," explained principal investigator Dr. Langston Holly, associate professor of neurosurgery at the David Geffen School of Medicine at UCLA. "While surgery can relieve the pressure and prevent further injury, it can’t repair damage to the cells and nerve fibers. We wanted to explore whether dietary supplementation could help the spinal cord heal itself."

The UCLA team studied two groups of rats with a condition that simulated cervical myelopathy — a progressive disorder that often occurs in people with spine-weakening conditions like rheumatoid arthritis and osteoporosis. Cervical myelopathy can lead to disabling neurological symptoms, such as difficulty walking, neck and arm pain, hand numbness and weakness of the limbs. It’s the most common cause of spine-related walking problems in people over 55.

The first group of animals was fed rat chow that replicated a Western diet high in saturated fats and sugar. The second group consumed a standard diet supplemented with docosahexaenoic acid, or DHA, and curcumin, a compound in turmeric, an Indian curry spice. A third set of rats received a standard rat diet and served as a control group.

Why these supplements? DHA is an omega-3 fatty acid shown to repair damage to cell membranes. Curcumin is a strong antioxidant that previous studies have linked to tissue repair. Both reduce inflammation.

"The brain and spinal cord work together, and years of research demonstrate that supplements like DHA and curcumin can positively influence the brain," said coauthor Fernando Gomez-Pinilla, professor of neurosurgery. "We suspected that what works in the brain may also work in the spinal cord. When we were unable to find good data to support our hypothesis, we decided to study it ourselves."

The researchers recorded a baseline of the rats walking and re-examined the animals’ gait on a weekly basis. As early as three weeks, the rats eating the Western diet demonstrated measurable walking problems that worsened as the study progressed. Rats fed a diet enriched with DHA and curcumin walked significantly better than the first group even six weeks after the study’s start.

Next, the scientists examined the rats’ spinal cords to evaluate how diet affected their injury on a molecular level. The researchers measured levels of three markers respectively linked to cell-membrane damage, neural repair and cellular communication.

The rats that ate the Western diet showed higher levels of the marker linked to cell-membrane damage. In contrast, the DHA and curcumin appeared to offset the injury’s effect in the second group, which displayed equivalent marker levels to the control group.

Levels of the markers linked to neural repair and cellular communication were significantly lower in the rats raised on the Western diet. Again, levels in the animals fed the supplemented diet appeared similar to those of the control group.

"DHA and curcumin appear to invoke several molecular mechanisms that preserved neurological function in the rats," said Gomez-Pinilla. "This is an exciting first step toward understanding the role that diet plays in protecting the body from degenerative disease."

"Our findings suggest that diet can help minimize disease-related changes and repair damage to the spinal cord," said Holly. "We next want to look at other mechanisms involved in the cascade of events leading up to chronic spinal-cord injury. Our goal is to identify which stages will respond best to medical intervention and identify effective steps for slowing the disease process."

Source: Science Daily

ScienceDaily (June 26, 2012) — Researchers have long been interested in discovering the ways that human brains represent thoughts through a complex interplay of electrical signals. Recent improvements in brain recording and statistical methods have given researchers unprecedented insight into the physical processes under-lying thoughts. For example, researchers have begun to show that it is possible to use brain recordings to reconstruct aspects of an image or movie clip someone is viewing, a sound someone is hearing or even the text someone is reading.

Researchers have long been interested in discovering the ways that human brains represent thoughts through a complex interplay of electrical signals. (Credit: © James Steidl / Fotolia)

A new study by University of Pennsylvania and Thomas Jefferson University scientists brings this work one step closer to actual mind reading by using brain recordings to infer the way people organize associations between words in their memories.

The research was conducted by professor Michael J. Kahana of the Department of Psychology in Penn’s School of Arts and Sciences and graduate student Jere-my R. Manning, then a member of the Neuroscience Graduate Group in Penn’s Perelman School of Medicine. They collaborated with other members of Kahana’s laboratory, as well as with research faculty at Thomas Jefferson University Hospital.

Their study was published in The Journal of Neuroscience.

The brain recordings necessary for the study were made possible by the fact that the participants were epilepsy patients who volunteered for the study while awaiting brain surgery. These participants had tiny electrodes implanted in their brains, which allowed researchers to precisely observe electrical signals that would not have been possible to measure outside the skull. While recording these electrical signals, the researchers asked the participants to study lists of 15 randomly chosen words and, a minute later, to repeat the words back in which-ever order they came to mind.

The researchers examined the brain recordings as the participants studied each word to home in on signals in the participant’ brains that reflected the meanings of the words. About a second before the participants recalled each word, these same “meaning signals” that were identified during the study phase were spontaneously reactivated in the participants’ brains.

Because the participants were not seeing, hearing or speaking any words at the times these patterns were reactivated, the researchers could be sure they were observing the neural signatures of the participants’ self-generated, internal thoughts.

Critically, differences across participants in the way these meaning signals were reactivated predicted the order in which the participants would recall the words. In particular, the degree to which the meaning signals were reactivated before recalling each word reflected each participant’s tendency to group similar words (like “duck” and “goose”) together in their recall sequence. Since the participants were instructed to say the words in the order they came to mind, the specific se-quence of recalls a participant makes provides insights into how the words were organized in that participant’s memory.

In an earlier study, Manning and Kahana used a similar technique to predict participants’ tendencies to organize learned information according to the time in which it was learned. Their new study adds to this research by elucidating the neural signature of organizing learned information by meaning.

"Each person’s brain patterns form a sort of ‘neural fingerprint’ that can be used to read out the ways they organize their memories through associations between words," Manning said.

The techniques the researchers developed in this study could also be adapted to analyze many different ways of mentally organizing studied information.

"In addition to looking at memories organized by time, as in our previous study, or by meaning, as in our current study, one could use our technique to identify neural signatures of how individuals organize learned information according to appearance, size, texture, sound, taste, location or any other measurable property," Manning said.

Such studies would paint a more complete picture of a fundamental aspect of human behavior.

"Spontaneous verbal recall is a form of memory that is both pervasive in our lives and unique to the human species," Kahana said. "Yet, this aspect of human memory is the least well understood in terms of brain mechanisms. Our data show a direct correspondence between patterns of brain activity and the meanings of individual words and show how this neural representation of meaning predicts the way in which one item cues another during spontaneous recall.

"Given the critical role of language in human thought and communication, identifying a neural representation that reflects the meanings of words as they are spontaneously recalled brings us one step closer to the elusive goal of mapping thoughts in the human brain."

Source: Science Daily

ScienceDaily (June 26, 2012) — Rhode Island Hospital researcher Suzanne de la Monte, M.D., has found a link between brain insulin resistance (diabetes) and two other key mediators of neuronal injury that help Alzheimer’s disease (AD) to propagate. The research found that once AD is established, therapeutic efforts must also work to reduce toxin production in the brain.

The study, “Dysfunctional Pro-Ceramide, ER Stress, and Insulin/IGF Signaling Networks with Progression of Alzheimer’s Disease”, is published in the June 22, 2012, supplement of the Journal of Alzheimer’s Disease.

Alzheimer’s disease is one of the most common degenerative dementias, and more than 115 million new cases are projected worldwide in the next 40 years. There is clinical and experimental evidence that treatment with insulin or insulin sensitizer agents can enhance cognitive function and in some circumstances help slow the rate of cognitive decline in AD. Alzheimer’s and other neurodegenerative diseases destroy the brain until the patients finally succumb. In order to effectively halt the process of neurodegeneration, the forces that advance and perpetuate the disease, particularly with regard to the progressive worsening of brain insulin/IGF resistance, must be understood.

"Brain insulin resistance (diabetes) is very much like regular diabetes," de la Monte said. "Since the underlying problems continue to be just about the same, we believe that the development of new therapies would be applicable for all types of diabetes, including Alzheimer’s disease, which we refer to as Type III diabetes."

She continued, “This study points out that once AD is established, therapeutic efforts should target several different pathways — not just one. The reason is that a positive feedback loop gets going, making AD progress. We have to break the vicious cycle. Restoring insulin responsiveness and insulin depletion will help, but we need to reduce brain stress and repair the metabolic problems that cause the brain to produce toxins.”

Ultimately, these findings will help to expand ways to both detect and treat AD.

Growing evidence supports the concept that AD is fundamentally a metabolic syndrome that leads to abnormalities linked to brain insulin and insulin-like growth factor (IGF) resistance. In AD, brain insulin and IGF resistance and deficiencies begin early and worsen with severity of the disease. The rationale behind the progression of the disease is that insulin-resistance dysregulates lipid metabolism and promotes ceramide accumulation, thereby increasing inflammation and lipid metabolism, causing toxic ceramides to accumulate in the brain. The end result is increased stress that threatens the survival and function of neurons in the brain.

The present study was designed to gain a better understanding of how brain insulin resistance becomes progressive and contributes to the neurodegeneration in AD, focusing on the roles of ceramides and stress. The researchers studied the same brain samples used previously to demonstrate progressive impairments in brain insulin/IGF signaling with increasing severity of AD.

Source: Science Daily

June 26, 2012

The inexorable spread of Alzheimer’s disease through the brain leaves dead neurons and forgotten thoughts in its wake. Researchers at Linköping University in Sweden are the first to show how toxic proteins are transferred from neuron to neuron.

Two nerve cells, each about 10 micrometers large, are visible as shadows in this picture. From the beginning only the right one (yellow arrow) contained the toxic, red stained, oligomeric beta-amyloid. When these sick cells make contacts with the healthy, green labeled cells (black arrow), toxic beta-amyloid will spread through the neuronal projections (white arrow). Subsequently, also the green cell will become sick. Credit: Martin Hallbeck

Through experiments on stained neurons, the research team – under the leadership of Martin Hallbeck, associate professor of Pathology – has been able to depict the process of neurons being invaded by diseased proteins that are then passed on to nearby cells.

"The spread of Alzheimer’s, which can be studied in the brains of diseased patients, always follows the same pattern. But until now how and why this happens has not been understood," says Hallbeck, who along with his research group has now published their results in The Journal of Neuroscience.

The illness starts in the entorhinal cortex – a part of the cerebral cortex, and then spreads to the hippocampus. Both of these areas are important for memory. Gradually, pathological changes take place in more and more areas of the brain, while the patient becomes even sicker.

Two proteins have been identified in connection with Alzheimer’s: beta amyloid and tau. Normally tau is found in the axons – the outgrowths that connect between neurons – where it has a stabilising function, while beta amyloid seems to have a role in the synapses where the neurons transfer signal substances to each other. But in Alzheimer’s patients, something happens with these proteins; autopsies reveal abnormal accumulations of both.

Why they become abnormal is still unknown, but what is known is that it’s not the large accumulations, or plaques, that damage the neurons. Instead, smaller groups of beta amyloid – called oligomeres – seem to be the toxic form that gradually destroy the neurons and shrink the brain.

"We wanted to investigate whether these oligomeres can spread from neuron to neuron, something many researchers tried earlier but didn’t succeed," Hallbeck says.

The study was inaugurated with an experiment on neuron cultures, where researchers injected oligomeres stained with a phosphorescent red substance called TMR using a very thin needle. The next day the neighbouring, connected neurons were also red, which showed that the oligomeres had spread.

To test whether a sick neuron can “infect” others, they conducted a round of experiments with mature human neurons stained green and mixed with others that were red after having taken up stained oligomeres. After a day, approximately half of the green cells had been in contact with a few of the red ones. After two more days, the axons had lost their shape and organelles in the cell nucleus had started to leak.

"Gradually more and more of the green cells became sick. Those that hadn’t taken up the oligomeres, on the other hand, weren’t affected," Hallbeck says.

The study is a breakthrough in understanding Alzheimer’s and its progress. If a way of stopping the transfer can be found, it could lead to a more effective inhibitor against the disease.

Provided by Linköping University

Source: medicalxpress.com

June 26, 2012

A new video article in JoVE, the Journal of Visualized Experiments, describes a novel procedure to monitor brain function and aid in functional mapping of patients with diseases such as epilepsy. This procedure illustrates the use of pre-placed electrodes for cortical mapping in the brains of patients who are undergoing surgery to minimize the frequency of seizures. This technique, while invasive, provides real-time analysis of brain function at a much higher resolution than current technologies.

This image shows the implanted electrodes as they are mapped on the brain. Credit: Journal of Visualized Experiments

Typically, functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) are used in neuroimaging studies but these techniques suffer from low temporal and spatial resolution. By using electrodes implanted in the brain of an epileptic patient already undergoing treatment, scientists can now image the brain with a much higher spatial resolution, lower signal interference, and a higher temporal resolution than fMRI or EEG.

The leading author of the study, Dr. Gerwin Schalk, from the New York State Department of Health and Albany Medical College, states, “Essentially, we have created a new imaging technique. Our procedure is innovative because it is prospective, meaning, it can image brain function as it occurs. Further, it does not require an expert to derive meaningful information concerning brain function.” He also notes that it was crucial for this procedure to be demonstrated in a video format. “The procedure is a very visual process. The ancillary information such as the spatial relationships of different components, the set-up of the hospital room, and the set-up of the equipment itself cannot be represented in a typical print article. The video capacities of JoVE were an excellent vehicle to demonstrate both the general set-up and the specific implementation of the mapping system.”

By relying on an epileptic patient’s neural implants, scientists gain an unprecedented insight into the brain’s function. Dr. Schalk’s procedure provides a technological advancement that can be applied in many ways, including stroke patient monitoring and rehabilitation, signal mapping and transduction for movement of prosthetic limbs, and enhancement of communication in individuals with paralysis of the vocal musculature. The JoVE video article provides a comprehensive demonstration of the new technique, from mapping the electrical implants to interpreting the tests in real time. JoVE editor Dr. Claire Standen emphasizes, “The new imaging technique demonstrated in this article is very important. There is a definite need for better, more accurate, imaging to monitor brain function. This technique can be applied to a wide range of clinical areas within the Neuroscience field.” The article can be found here: Recording Human Electrocorticographic (ECoG) Signals for Neuroscientific Research and Real-time Functional Cortical Mapping

Provided by The Journal of Visualized Experiments

Source: medicalxpress.com

June 25, 2012

The same neurological mechanism involved in the transition from habitual to compulsive drug use could underlie less severe, but still harmful, compulsive behaviours.

"We’re trying to understand individuality in addictive behaviour. Many people can be exposed to drugs with addictive potential, for instance, but not everyone will become addicted,” explains Eric Dumont, an associate professor in the Department of Biomedical and Molecular Sciences. “We believe we’ve identified a mechanism that makes certain people predisposed to developing addictions, and it’s possible that the same mechanism underlies many - perhaps most - compulsive behaviours.”

The mechanism occurs in a reward pathway of the brain. In this pathway, the brain maintains a delicate balance between pleasure and aversion, ensuring that moment-to-moment desires and dislikes remain in sync with the biological needs of the body.

Dr. Dumont and his team found unusual activity in this pathway when modeling drug addiction in rats, which exhibit a genetic predisposition to addiction comparable to humans. They believe that the pathway’s balance is prone to becoming unbalanced in a certain percentage of the population. The signal to stop an activity reverses to a green light.

The team hopes that by identifying this mechanism, and possibly others like it, they will allow researchers to better understand and monitor a range of compulsive behaviours. Accordingly, Dr. Dumont’s team collaborates with Dr. Cella Olmstead, associate professor of Psychology at Queen’s, who recently developed an animal model of compulsive sucrose intake.

Dr. Dumont and this team were recently awarded a $520,000 operating grant from Canadian Institutes of Health Research (CIHR) to support their work for the next five years in understanding the neurological processes behind addiction behaviour.

Provided by Queen’s University

Source: medicalxpress.com

ScienceDaily (June 25, 2012) — The hot flashes and night sweats that most women experience early in menopause are not linked to increased levels of cardiovascular disease risk markers unless the symptoms persist or start many years after menopause begins. These new study results were presented June 23 at The Endocrine Society’s 94th Annual Meeting in Houston.

"Our study provides reassurance that the common experience of menopausal symptoms in early menopause is not associated with increases in blood pressure or other risk markers for cardiovascular disease," said lead researcher Emily Szmuilowicz, MD, an assistant professor at Northwestern University’s medical school in Chicago.

Researchers have questioned whether vasomotor menopausal symptoms such as hot flashes and night sweats reflect poor cardiovascular health. However, a 2011 study by Szmuilowicz and co-workers found that women who experienced menopausal symptoms only at the onset of menopause were less likely to have a stroke or heart attack or to die than were women who experienced hot flashes late in menopause or who did not have hot flashes at all.

Their new study focused on markers in the body that have been linked to a raised risk of cardiovascular disease. The risk markers examined were blood pressure, cholesterol, insulin, glucose (blood sugar) and blood markers of abnormal blood vessel function. Because inflammation is common in people with heart disease or stroke, the group also looked at blood markers of inflammation, including white blood cell count — the number of disease-fighting cells.

This study used retrospective data from nearly 60,000 postmenopausal women who participated in the Women’s Health Initiative Observational Study. The ongoing study, funded by the National Institutes of Health, is examining the relationships between health outcomes and new risk indicators for disease.

The researchers grouped women into four categories based on timing of their menopausal symptoms of hot flashes and night sweats: only at the start of menopause (early-onset menopausal symptoms), only years later in menopause (late-onset menopausal symptoms), both time periods (persistent menopausal symptoms), and not at all.

The investigators found no association between early-onset vasomotor menopausal symptoms and increased levels of any cardiovascular risk markers. However, both persistent and late-onset menopausal symptoms were associated with higher blood pressure and higher white blood cell count compared with women without menopausal symptoms, they reported. Persistent menopausal symptoms also correlated with higher levels of glucose and insulin, which are markers for diabetes.

It is unclear why women who experience menopausal symptoms at different stages of menopause may have differing levels of cardiovascular disease risk, Szmuilowicz said She speculated that “if menopausal symptoms occur long after menopause begins, this may signal a blood vessel abnormality that could also affect cardiovascular health.”

Source: Science Daily

ScienceDaily (June 25, 2012) — Deep brain stimulation reduces binge eating in mice, suggesting that this surgery, which is approved for treatment of certain neurologic and psychiatric disorders, may also be an effective therapy for obesity. Presentation of the results took place June 25 at The Endocrine Society’s 94th Annual Meeting in Houston.

"Doing brain surgery for obesity treatment is a controversial idea," said the study’s presenting author, Casey Halpern, MD, a fifth-year neurosurgery resident physician at the University of Pennsylvania, Philadelphia. "However, binge eating is a common feature of obese patients that frequently is associated with suboptimal treatment outcomes."

Currently the U.S. Food and Drug Administration has approved deep brain stimulation for use in various conditions that affect the brain, including Parkinson’s disease and essential tremor. The procedure does not destroy any part of the brain and typically does not cause pain, Halpern said.

Available treatments of obesity may inadequately address the neural basis of this compulsive overeating behavior, he suggested. A region of the brain called the nucleus accumbens is known to be dysregulated in both rodents and people who binge eat. Therefore, Halpern and his co-workers targeted that brain region with deep brain stimulation in a strain of obesity-prone mice.

The surgery involved implanting an electrode in the nucleus accumbens. Wires connected the electrode to an external neurostimulator, a device similar to a pacemaker. When switched on, the stimulator triggers the electrode to deliver continuous electrical pulses to the brain.

After recovery from surgery, the mice received high-fat food at the same time every day for one hour, and the researchers measured their food consumption. Binge eating was defined as consuming 25 percent or more of the usual daily caloric intake during this period.

For one week, mice consistently binged, eating almost half of their daily calories during this one hour, the authors reported. Then on alternating days, the investigators turned on the stimulator. On the days that deep brain stimulation was administered, or “on,” the scientists observed a significant (approximately 60 percent) decrease in consumption of the high-fat diet. On the alternate days when they turned off the stimulator, binge eating returned, Halpern said.

The researchers then studied how deep brain stimulation might work to improve binge eating. With medications, they blocked various receptors of dopamine neurons, or nerve cells. Dopamine is a brain neurotransmitter, a chemical messenger, whose release in the brain is linked to the desire for rewarding behaviors such as eating high-fat food, according to Halpern.

Only one of the medications had an effect. Raclopride, which blocks the type 2 dopamine receptor, weakened the beneficial effect of deep brain stimulation by 50 percent.

Their results, Halpern said, showed that “at least one way that deep brain stimulation functions to suppress binge eating might be by modulating activity of neurons expressing the type 2 dopamine receptor.”

Source: Science Daily

June 25, 2012 By Rick Nauert

A new study involving children with Williams syndrome (WS) suggests that improved regulation of oxytocin and vasopressin may someday improve care for autism, anxiety, post-traumatic stress disorder and WS.

WS results when certain genes are absent because of a faulty recombination event during the development of sperm or egg cells. Virtually everyone with WS has exactly the same set of genes missing (25 to 28 genes are missing from one of two copies of chromosome 7).

“The genetic deficiencies allow researchers to examine the genetic and neuronal basis of social behavior,” said Ursula Bellugi, Ph.D., a co-author on the paper.

“This study provides us with crucial information about genes and brain regions involved in the control of oxytocin and vasopressin, hormones that may play important roles in other disorders.”

In the study, scientists at the Salk Institute for Biological Studies and the University of Utah, found that people with WS flushed with the hormones oxytocin and arginine vasopressin (AVP) when exposed to emotional triggers.

Children with WS love people, despite being challenged with numerous health problems. WS kids are extremely gregarious, irresistibly drawn to strangers, and insist on making eye contact.

They have an affinity for music. But they also experience heightened anxiety, have an average IQ of 60, experience severe spatial-visual problems, and suffer from cardiovascular and other health issues.

Yet despite their desire to befriend people, WS kids have difficulty creating and maintaining social relationships — an issue that obviously affects many people without WS.

In the new study, led by Julie R. Korenberg, M.D., 21 participants, 13 who have WS and a control group of eight people without the disorder were evaluated at the Cedars-Sinai Medical Center in Los Angeles. Because music is a known strong emotional stimulus, the researchers asked participants to listen to music.

Before the music was played, the participants’ blood was drawn to determine a baseline level for oxytocin. Remarkably, those with WS had three times as much of the hormone as those without the syndrome.

Blood also was drawn at regular intervals while the music played and was analyzed afterward to check for real-time, rapid changes in the levels of oxytocin and AVP.

While other studies have examined how oxytocin affects emotion when artificially introduced into people, such as through nasal sprays, this is one of the first significant studies to measure naturally occurring changes in oxytocin levels in rapid, real time as people undergo an emotional response.

Although the WS participants displayed little outward response to the music, an analyses of blood samples showed that the oxytocin levels, and to a lesser degree AVP, had increased sharply while they had listened to the music.

In contrast, among those without WS, both the oxytocin and AVP levels remained largely unchanged as they listened to music.

Korenberg believes the blood analyses strongly indicate that oxytocin and AVP are not regulated correctly in people with WS, and that the behavioral characteristics unique to people with WS are related to this problem. “This shows that oxytocin quite likely is very involved in emotional response,” she said.

In addition to listening to music, study participants already had taken three social behavior tests that evaluate willingness to approach and speak to strangers, emotional states, and various areas of adaptive and problem behavior.

Those test results suggest that increased levels of oxytocin are linked to both increased desire to seek social interaction and decreased ability to process social cues, a double-edged message that may be very useful at times, for example, during courtship, but damaging at others, as in WS.

“The association between abnormal levels of oxytocin and AVP and altered social behaviors found in people with Williams Syndrome points to surprising, entirely unsuspected deleted genes involved in regulation of these hormones and human sociability,” Korenberg said.

“It also suggests that the simple characterization of oxytocin as ‘the love hormone’ may be an overreach. The data paint a far more complicated picture.”

Overall, the researchers say, their findings paint a hopeful picture, and the study holds promise for speeding progress in treating WS, and perhaps autism and anxiety through regulation of these key players in human brain and emotion, oxytocin and vasopressin.

Source: PsychCentral

ScienceDaily (June 25, 2012) — Researchers have discovered how a hormone in the gut slows the rate at which the stomach empties and thus suppresses hunger and food intake. Results of the animal study were presented June 25 at The Endocrine Society’s 94th Annual Meeting in Houston.

"The gut hormone glucagon-like peptide 2, or GLP-2, functions as a neurotransmitter and fine-tunes gastric emptying through — as suspected — its receptor action in the brain," said the lead investigator, Xinfu Guan, PhD, assistant professor of pediatrics and medicine at Baylor College of Medicine in Houston.

The researchers found that this action occurs in the GLP-2 receptor specifically in a key group of nerve cells in the brain, called pro-opiomelanocortin, or POMC, neurons. These neurons are in the hypothalamus, the part of the brain that produces appetite-controlling neuropeptides.

In their study using molecular methods, mice lacking this GLP-2 receptor in the POMC neurons showed late-onset obesity and higher food intake compared with normal wild-type mice. The mutant, or GLP-2 receptor “knockout,” mice also had accelerated gastric emptying after a liquid meal, as found on a noninvasive breath test. The faster the gastric emptying, the higher the food intake, scientists know.

Therefore, obese people may have something wrong with this hormone receptor, which alters their gastric emptying rate, Guan speculated. Many studies have shown that nondiabetic, obese humans have accelerated gastric emptying.

The researchers also found that this receptor quickly activated the PI3K intracellular signaling pathway in the POMC neurons. This, in turn, induces neuronal excitation (transmission of signals) and gene expression, according to Guan.

These findings, Guan said, show that in the central nervous system the GLP-2 receptor plays an important physiological role in the control of food intake and gastric emptying.

"This study has advanced our understanding of the brain-gut neural circuits that mediate eating behavior via modulating gastric emptying, which contributes to the control of body weight," he said.

Source: Science Daily

ScienceDaily (June 25, 2012) — Women with moderate to severe depression had substantial improvement in their symptoms of depression after they received treatment for their vitamin D deficiency, a new study finds.

The case report series was presented June 23 at The Endocrine Society’s 94th Annual Meeting in Houston.

Because the women did not change their antidepressant medications or other environmental factors that relate to depression, the authors concluded that correction of the patients’ underlying shortage of vitamin D might be responsible for the beneficial effect on depression.

"Vitamin D may have an as-yet-unproven effect on mood, and its deficiency may exacerbate depression," said Sonal Pathak, MD, an endocrinologist at Bayhealth Medical Center in Dover, Del. "If this association is confirmed, it may improve how we treat depression."

Pathak presented the research findings in three women, who ranged in age from 42 to 66. All had previously diagnosed major depressive disorder, also called clinical depression, and were receiving antidepressant therapy. The patients also were being treated for either Type 2 diabetes or an underactive thyroid (hypothyroidism).

Because the women had risk factors for vitamin D deficiency, such as low vitamin D intake and poor sun exposure, they each underwent a 25-hydroxyvitamin D blood test. For all three women, the test found low levels of vitamin D, ranging from 8.9 to 14.5 nanograms per milliliter (ng/mL), Pathak reported. Levels below 21 ng/mL are considered vitamin D deficiency, and normal vitamin D levels are above 30 ng/mL, according to The Endocrine Society.

Over eight to 12 weeks, oral vitamin D replacement therapy restored the women’s vitamin D status to normal. Their levels after treatment ranged from 32 to 38 ng/mL according to the study abstract.

After treatment, all three women reported significant improvement in their depression, as found using the Beck Depression Inventory. This 21-item questionnaire scores the severity of sadness and other symptoms of depression. A score of 0 to 9 indicates minimal depression; 10 to 18, mild depression; 19 to 29, moderate depression; and 30 to 63, severe depression.

One woman’s depression score improved from 32 before vitamin D therapy to 12, a change from severe to mild depression. Another woman’s score fell from 26 to 8, indicating she now had minimal symptoms of depression. The third patient’s score of 21 improved after vitamin D treatment to 16, also in the mild range.

Other studies have suggested that vitamin D has an effect on mood and depression, but there is a need for large, good-quality, randomized controlled clinical trials to prove whether there is a real causal relationship, Dr Pathak said.

"Screening at-risk depressed patients for vitamin D deficiency and treating it appropriately may be an easy and cost-effective adjunct to mainstream therapies for depression," she said.

Source: Science Daily

ScienceDaily (June 25, 2012) — Widely available EEG testing can distinguish children with autism from neurotypical children as early as age 2, finds a study from Boston Children’s Hospital. The study is the largest, most rigorous study to date to investigate EEGs as a potential diagnostic tool for autism, and offers hope for an earlier, more definitive test.

Widely available EEG testing can distinguish children with autism from neurotypical children as early as age 2, finds a new study. The study is the largest, most rigorous study to date to investigate EEGs as a potential diagnostic tool for autism, and offers hope for an earlier, more definitive test. (Credit: © dule964 / Fotolia)

Researchers Frank H. Duffy, MD, of the Department of Neurology, and Heidelise Als, PhD, of the Department of Psychiatry at Boston Children’s Hospital, compared raw EEG data from 430 children with autism and 554 control subjects, ages 2 to 12, and found that those with autism had consistent EEG patterns indicating altered connectivity between brain regions — generally, reduced connectivity as compared with controls.

While altered connectivity occurred throughout the brain in the children with autism, the left-hemisphere language areas stood out, showing reduced connectivity as compared with neurotypical children, consistent with neuroimaging research. Findings were published June 26 in the online open-access journal BMC Medicine.

Duffy and Als focused on children with “classic” autism who had been referred for EEGs by neurologists, psychiatrists or developmental pediatricians to rule out seizure disorders. Those with diagnosed seizure disorders were excluded, as were children with Asperger’s syndrome and “high functioning” autism, who tend to dominate (and skew) the existing literature because they are relatively easy to study. The researchers also excluded children with genetic syndromes linked to autism (such as Fragile X or Rett syndrome), children being treated for other major illnesses, those with sensory disorders like blindness and deafness and those taking medications.

"We studied the typical autistic child seeing a behavioral specialist — children who typically don’t cooperate well with EEGs and are very hard to study," says Duffy. "No one has extensively studied large samples of these children with EEGs, in part because of the difficulty of getting reliable EEG recordings from them."

The researchers used techniques developed at Boston Children’s Hospital to get clean waking EEG recordings from children with autism, such as allowing them to take breaks. They used computer algorithms to adjust for the children’s body and eye movements and muscle activity, which can throw off EEG readings.

To measure connectivity in the brain, Duffy and Als compared EEG readings from multiple electrodes placed on the children’s scalps, and quantified the degree to which any two given EEG signals — in the form of waves — are synchronized, known as coherence. If two or more waves rise and fall together over time, it indicates that those brain regions are tightly connected. (Duffy likens coherence to two people singing “Mary Had a Little Lamb” together. If they can see and hear each other, they are more likely to sing in synchrony — so their coherence is high.)

In all, using computational techniques, the researchers generated coherence readings for more than 4,000 unique combinations of electrode signals, and looked for the ones that seemed to vary the most from child to child. From these, they identified 33 coherence “factors” that consistently distinguished the children with autism from the controls, across all age groups (2 to 4, 4 to 6, and 6 to 12 years).

Duffy and Als repeated their analysis 10 times, splitting their study population in half different ways and using half to identify the factors, and the other half to test and validate them. Each time, the classification scheme was validated.

"These factors allowed us to make a discriminatory rule that was highly significant and highly replicable," says Duffy. "It didn’t take anything more than an EEG — the rest was computational. Our choice of variables was completely unbiased — the data told us what to do."

The researchers believe the findings could be the basis for a future objective diagnostic test of autism, particularly at younger ages when behavior-based measures are unreliable. Their most immediate goal is to repeat their study in children with Asperger’s syndrome and see if its EEG patterns are similar to or different from autism. They also plan to evaluate children whose autism is associated with conditions such as tuberous sclerosis, fragile X syndrome and extremely premature birth.

Source: Science Daily

June 25, 2012 By Traci Pedersen

Scientists have found improvements on memory tests and an increase in brain volume in Chinese seniors who practice tai chi three times a week, according to an article published in the Journal of Alzheimer’s Disease.

The trial also showed increases in brain volume and smaller cognitive improvements in individuals that participated in lively discussions three times per week over the same time period.

Researchers from the University of South Florida and Fudan University in Shanghai conducted an eight-month randomized controlled trial involving a group of seniors who practiced tai chi as well as a group who participated in lively conversations.  Researchers compared these to a control group who received no intervention.

Previous studies have shown an increase in brain volume in people who participated in aerobic exercise, and in one of these trials, memory was improved as well.

However, this was the first trial to prove that a less aerobic form of exercise, tai chi, as well as stimulating discussion, led to similar increases in brain volume and improvements on psychological tests of memory and thinking.

Volunteers who did not participate in the interventions showed brain shrinkage during this time period, consistent with what generally has been observed for persons in their 60s and 70s.

Several studies have shown that dementia and the gradual cognitive decline that precedes it is linked to increasing shrinkage of the brain as nerve cells and their connections are slowly lost.

“The ability to reverse this trend with physical exercise and increased mental activity implies that it may be possible to delay the onset of dementia in older persons through interventions that have many physical and mental health benefits,” said lead author James Mortimer, Ph.D., professor of epidemiology at the University of South Florida College of Public Health.

Research suggests that aerobic exercise is associated with increased production of brain growth factors. It has been undetermined whether forms of exercise like tai chi that include an important mental exercise component could lead to similar changes in brain development.

“If this is shown, then it would provide strong support to the concept of ‘use it or lose it’ and encourage seniors to stay actively involved both intellectually and physically,” Mortimer said.

One question raised by the research is whether sustained physical and mental exercise can help prevent Alzheimer’s disease.

“Epidemiologic studies have shown repeatedly that individuals who engage in more physical exercise or are more socially active have a lower risk of Alzheimer’s disease,” Mortimer said. “The current findings suggest that this may be a result of growth and preservation of critical regions of the brain affected by this illness.”

Source: PsychCentral

ScienceDaily (June 25, 2012) — A team of researchers led by an epidemiologist at Mount Sinai School of Medicine and University of Iceland has found a correlation between the age at which children with attention-deficit/hyperactivity disorder (ADHD) begin taking medication, and how well they perform on standardized tests, particularly in math.

The study, titled, “A Population-Based Study of Stimulant Drug Treatment of ADHD and Academic Progress in Children,” appears in the July, 2012, edition of Pediatrics, and can be viewed online on June 25. Using data from the Icelandic Medicines Registry and the Database of National Scholastic Examinations, the researchers studied 11,872 Icelandic children born between 1994 and 1996. The children started medication for ADHD at different times between fourth and seventh grades.

The findings showed that children who began drug treatment within 12 months of their fourth-grade test declined 0.3 percent in math by the time they took their seventh-grade test, compared with a decline of 9.4 percent in children who began taking medication 25-to-36 months after their fourth-grade test.

The data also showed that girls benefited only in mathematics, whereas boys had marginal benefits in math and language arts.

"Children who began taking medications immediately after their fourth-grade standardized tests showed the smallest declines in academic performance," said the study’s lead author Helga Zoega, PhD, Post Doctoral Fellow of Epidemiology at Mount Sinai’s Institute for Translational Epidemiology. "The effect was greater in girls than boys and also greater for children who did poorly on their fourth grade test."

Stimulants are widely used in the United States as a therapeutic option for children with inattention, impulsivity, and hyperactivity associated with ADHD. The medications are less frequently used in Europe, although their use in Iceland most closely resembles the U.S. Long-term follow-up studies of stimulant use and academic performance are scarce, according to the researchers.

Source: Science Daily

June 25, 2012

The Allen Institute for Brain Science convened the first ever Allen Brain Atlas Hackathon last week, opening its doors to a diverse group of programmers and informatics experts for a non-stop week of collaboration, learning and coding based on its public online platform of data, tools and source code. The event brought together more than 30 participants from top universities and institutes ranging from the Baylor College of Medicine in Houston to the Nencki Institute of Experimental Biology in Poland, as well as from start-ups and established technology companies, to develop data analysis strategies and tools based on the newly enhanced Allen Brain Atlas application programming interface (API).

"This hackathon stems from our longstanding, open approach to science and our belief that putting our data-rich resources in the hands of the many and varied experts around the globe is the most effective way to drive progress in brain research,” said Chinh Dang, Chief Technology Officer of the Allen Institute for Brain Science. “The hackathon projects delivered innovative ways of handling data, offering direct contributions to the informatics and programming communities as well as to neuroscience. We hope that this event serves as a springboard for others out in the community to use our API, and we look forward to seeing what can be done with it.”

The Allen Institute for Brain Science is one of the biggest data producers in neuroscience, with rapidly growing data stores in the petabyte range that it makes publicly available through its Web-based Allen Brain Atlas resources. These resources include, among others, anatomically and genomically comprehensive maps of genes at work in the mouse and human brains and receive approximately 50,000 visits each month from researchers around the globe.

The public API was created as an additional form of data sharing to spur community technology development and further empower scientists to make groundbreaking discoveries about the brain in health and disease—including insights into learning, cognition, development, Alzheimer’s, obesity, schizophrenia, autism, and more—that will deliver better treatment options sooner. The hackathon coincided with the public release of the full Allen Brain Atlas API earlier this month, and a key goal of the event was to ignite community momentum and interest in using it.

Using the Allen Brain Atlas API, developers can create entirely new software applications, mashups and novel data mining tools for making sense of the large and ever-growing volumes of neuroscience data. The API offers data access across species, ages, disease and control states, providing a powerful means to compare many types of data (e.g., histology images, gene expression, and MRI) among many types of samples (e.g., ages, species or diseases).

"The Allen Institute is a leader in large-scale open science, known for providing high-quality data and online tools that advance brain research," said Sean Hill, Executive Director of the International Neuroinformatics Coordinating Facility (INCF). "With the Allen Brain Atlas Hackathon and their public API, they are bringing the same collaborative, community-focused approach to technology development and innovation that is at the core of INCF’s mission."

The hackathon program was designed to provide scientists and programmers a solid foundation in using the Allen Brain Atlas API for data mining, data analysis and tools development. The event featured a handful of speakers from the Allen Institute, as well as external experts who had leveraged earlier versions of the API in their work. As a hands-on workshop, participants spent most of the time working on projects of their choice. The Allen Institute development team actively participated throughout the week to provide specific examples of API usage, as well as to team up with community participants to develop collaborative projects. Participants’ presentations throughout the week showcased their projects and progress, stimulating new ideas and benefiting from the collective feedback and troubleshooting power of the entire group.

Projects ranged from practical applications, such as using a list of glioblastoma-related genes to discover biological patterns that could shed new light on the biology of the disease and developing strategies to use gene expression data with functional brain scanning technologies, to purely creative applications, including translating genomic data into music.

The Allen Brain Atlas Hackathon was hosted by the Allen Institute for Brain Science and funded jointly with the International Neuroinformatics Coordinating Facility (INCF).

Provided by Allen Institute for Brain Science

Source: medicalxpress.com

June 24, 2012 by SETH BORENSTEIN

(AP) — The more we study animals, the less special we seem.

In this Dec. 13, 2006 photo provided by the Primate Research Institute of Kyoto University, a 5 1/2-year-old chimpanzee named Ayumu performs a memory test with randomly-placed consecutive Arabic numerals, which are later masked, accurately duplicating the lineup on a touch screen computer in Kyoto, Japan. The young chimpanzees in the study titled “Working memory of numerals in chimpanzees” by Sana Inoue and Tetsuro Matsuzawa could memorize the nine numerals much faster and more accurately than human adults. The evidence that animals are more intelligent and more social than we thought seems to grow each year, especially when it comes to primates. It’s an increasingly hot scientific field with the number of ape and monkey cognition studies doubling in recent years, often with better technology and neuroscience paving the way to unusual discoveries. (AP Photo/Primate Research Institute of Kyoto University) PART OF A SEVEN-PICTURE PACKAGE WITH “ANIMAL SCIENCES”

Baboons can distinguish between written words and gibberish. Monkeys seem to be able to do multiplication. Apes can delay instant gratification longer than a human child can. They plan ahead. They make war and peace. They show empathy. They share.

"It’s not a question of whether they think — it’s how they think," says Duke University scientist Brian Hare. Now scientists wonder if apes are capable of thinking about what other apes are thinking.

The evidence that animals are more intelligent and more social than we thought seems to grow each year, especially when it comes to primates. It’s an increasingly hot scientific field with the number of ape and monkey cognition studies doubling in recent years, often with better technology and neuroscience paving the way to unusual discoveries.

Read More →

ScienceDaily (June 24, 2012) — The blood-brain barrier — the filter that governs what can and cannot come into contact with the mammalian brain — is a marvel of nature. It effectively separates circulating blood from the fluid that bathes the brain, and it keeps out bacteria, viruses and other agents that could damage it.

But the barrier can be disrupted by disease, stroke and multiple sclerosis, for example, and also is a big challenge for medicine, as it can be difficult or impossible to get therapeutic molecules through the barrier to treat neurological disorders.

Now, however, the blood-brain barrier may be poised to give up some of its secrets as researchers at the University of Wisconsin-Madison have created in the laboratory dish the cells that make up the brain’s protective barrier. Writing in the June 24, 2012 edition of the journal Nature Biotechnology, the Wisconsin researchers describe transforming stem cells into endothelial cells with blood-brain barrier qualities.

Access to the specialized cells “has the potential to streamline drug discovery for neurological disease,” says Eric Shusta, a UW-Madison professor of chemical and biological engineering and one of the senior authors of the new study. “You can look at tens of thousands of drug candidates and just ask the question if they have a chance to get into the brain. There is broad interest from the pharmaceutical industry.”

The blood-brain barrier depends on the unique qualities of endothelial cells, the cells that make up the lining of blood vessels. In many parts of the body, the endothelial cells that line capillaries are spaced so that substances can pass through. But in the capillaries that lead to the brain, the endothelial cells nestle in tight formation, creating a semi-permeable barrier that allows some substances — essential nutrients and metabolites — access to the brain while keeping others — pathogens and harmful chemicals — locked out.

The cells described in the new Wisconsin study, which was led by Ethan S. Lippmann, now a postdoctoral fellow at the Wisconsin Institute for Discovery, and Samira M. Azarin, now a postdoctoral fellow at Northwestern University, exhibit both the active and passive regulatory qualities of those cells that make up the capillaries of the intact brain.

The research team coaxed both embryonic and induced pluripotent stem cells to form the endothelial cells of the blood-brain barrier. The use of induced cells, which can come from patients with specific neurological conditions, may be especially important for modeling disorders that compromise the blood-brain barrier. What’s more, because the cells can be mass produced, they could be used to devise high-throughput screens for molecules that may have therapeutic value for neurological conditions or to identify existing drugs that may have neurotoxic qualities.

"The nice thing about deriving endothelial cells from induced pluripotent stem cells is that you can make disease-specific models of brain tissue that incorporate the blood-brain barrier," explains Sean Palecek, a UW-Madison professor of chemical and biological engineering and a senior author of the new report. "The cells you create will carry the genetic information of the condition you want to study."

The generation of the specialized blood-brain barrier endothelial cells, the Wisconsin researchers note, has never been done with stem cells. In addition to the potential applications to screen drugs and model pathologies of the blood-brain barrier, they may also provide a novel window for developmental biologists who are interested in how the barrier comes together and co-develops with the brain.

"Neurons develop at the same time as the endothelial cells," Shusta says, noting that, in development, the cells secrete chemical cues that help determine organ specificity.

"We don’t know what all those factors are," Lippmann says. "But with this model, we can go back and look." Identifying all of the molecular factors at play as blank slate stem cells differentiate to become specialized endothelial cells could one day have clinical significance to treat stroke or tamp down the ability of brain tumors to recruit blood vessels needed to sustain cancer.

Source: Science Daily

ScienceDaily (June 24, 2012) — Every day the human brain is presented with tasks ranging from the trivial to the complex. How much mental effort and attention are devoted to each task is usually determined in a split second and without conscious awareness. Now a study from Massachusetts General Hospital (MGH) researchers finds that a structure deep within the brain, believed to play an important role in regulating conscious control of goal-directed behavior, helps to optimize behavioral responses by predicting how difficult upcoming tasks will be. The report is receiving advance online publication in Nature.

"The dorsal anterior cingulate cortex (dACC), which lies deep beneath the outer layer of the frontal lobes, is part of an ancient and enigmatic part of the brain," says Emad Eskandar, MD, of the MGH Department of Neurosurgery, senior author of the Nature paper. “Some have speculated that it plays a role in detecting errors or monitoring for conflicting demands, but exactly how it contributes to regulating behavioral responses is unclear, so we used a variety of scientific techniques to get a better picture of its function.”

The study enrolled six participants who were scheduled to undergo cingulotomy — a procedure in which a small, precisely placed lesion is created within the ACC — to treat severe obsessive compulsive disorder (OCD) that has not responded to other types of treatment. A standard part of the cingulotomy procedure involves microelectrode recordings of the activity of single neurons in the area where the lesion is to be placed. To evaluate dACC function, the investigators recorded brain activity from several neurons within the structure while participants performed a behavioral task testing their reactions to visual images.

The task presented participants with a random series of images of three numerals, which could be 0, 1, 2, or 3. In each image, two of the numerals were identical. Participants responded by pressing one of three buttons, the position of which would indicate the identity of the number that was different, with the left button indicating 1, the middle 2 and the right button 3. Each image was ranked in difficulty depending on how much the position of the target numeral or the identity of the duplicate numerals might distract participants from the correct response. For example, when presented with 3-3-2, the correct response would be to press the middle button for number 2; and that image would be ranked more difficult than 3-2-3, in which both the target number and the correct button were in the same position.

Functional magnetic resonance imaging (fMRI) of four participants performing the behavioral task prior to the cingulotomy procedure revealed that the task increased metabolic activity within the dACC, a result seen in previous fMRI studies. The fMRI images also revealed that responding to more difficult images produced greater activity levels within the dACC and in other structures known to be involved in decision making. Intraoperative microelectrode recordings of all participants demonstrated that this apparent increase in metabolic activity corresponded with an increase in neuronal activity, linking for the first time the increased activation revealed by fMRI with increased neuronal firing.

Analysis of individual neuron activity indicated that dACC neuronal activity remained elevated immediately after difficult trials. Moreover, participant reaction time revealed that the difficulty of the prior trial had an impact on the next trial: if the preceding trial was of the same level of difficulty, reaction time was shorter; if the two tests were of different difficulty levels — even if the second test was easier — reaction time was longer. By anticipating the difficulty of upcoming tasks, the authors note, it appears that the dACC speeds up responses when difficulty levels are constant but slows response time down when faced with changing demands in order to promote accuracy.

While behavioral tests conducted after the cingulotomy procedure — which destroys tissue within the dACC — did not indicate a change in participants’ ability to perform the test accurately, the impact of preceding trials on reaction time appeared to vanish. “Participants could still perform the task, but the dACC’s role of priming the system based on immediate prior experience was gone,” Eskandar explains. “We believe this result indicates an important role for the dACC in rapidly adjusting to different cognitive demands, possibly by recruiting other areas of the brain to solve particular problems.”

An associate professor of Surgery at Harvard Medical School, Eskandar adds that, while significant cognitive changes have not been reported in patients undergoing cingulotomy, the apparent role of the dACC in adapting to changing situations implies a possible role for the structure in several psychiataric disorders. “A lack of behavior flexibility and adjustment is characteristic of OCD, for example. Whether or not our findings directly relate to these disorders remains to be determined, but we hope that continued study using complex tasks, such as the behavioral test used here, will be helpful in diagnosing or monitoring psychiatric disorders.”

Source: Science Daily

ScienceDaily (June 24, 2012) — Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.

This image depicts hemimegalencephaly. (Credit: UC San Diego School of Medicine)

In a paper published in the June 24, 2012 online issue of Nature Genetics, a team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.

De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings — a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues — suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.

Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analyzing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.

"Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition," said Gleeson. Realizing they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.

The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.

"We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly," said Gleeson. "These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers."

The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.

"Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere," said Mathern. "Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere."

But a less-invasive drug therapy would still be more appealing.

"We know that certain already-approved medications can turn down the signaling pathway used by the mutated genes in hemimegalencephaly," said lead author and former UC San Diego post-doctoral researcher Jeong Ho Lee, now at the Korea Advanced Institute of Science and Technology. "We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?"

Source: Science Daily

ScienceDaily (June 24, 2012) — Researchers at Yale School of Medicine have zeroed in on a set of neurons in the part of the brain that controls hunger, and found that these neurons are not only associated with overeating, but also linked to non-food associated behaviors, like novelty-seeking and drug addiction.

A lean animal and a control were both exposed to a novelty item (center). The lean animal spent more time exploring the novelty, as shown by the higher concentration of yellow in the slide. (Credit: Image courtesy of Yale University)

Published in the June 24 online issue of Nature Neuroscience, the study was led by Marcelo O. Dietrich, postdoctoral associate, and Tamas L. Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine.

In attempts to develop treatments for metabolic disorders such as obesity and diabetes, researchers have paid increasing attention to the brain’s reward circuits located in the midbrain, with the notion that in these patients, food may become a type of “drug of abuse” similar to cocaine. Dietrich notes, however, that this study flips the common wisdom on its head.

"Using genetic approaches, we found that increased appetite for food can actually be associated with decreased interest in novelty as well as in cocaine, and on the other hand, less interest in food can predict increased interest in cocaine," said Dietrich.

Horvath and his team studied two sets of transgenic mice. In one set, they knocked out a signaling molecule that controls hunger-promoting neurons in the hypothalamus. In the other set, they interfered with the same neurons by eliminating them selectively during development using diphtheria toxin. The mice were given various non-invasive tests that measured how they respond to novelty, and anxiety, and how they react to cocaine.

"We found that animals that have less interest in food are more interested in novelty-seeking behaviors and drugs like cocaine," said Horvath. "This suggests that there may be individuals with increased drive of the reward circuitry, but who are still lean. This is a complex trait that arises from the activity of the basic feeding circuits during development, which then impacts the adult response to drugs and novelty in the environment."

Horvath and his team argue that the hypothalamus, which controls vital functions such as body temperature, hunger, thirst fatigue and sleep, is key to the development of higher brain functions. “These hunger-promoting neurons are critically important during development to establish the set point of higher brain functions, and their impaired function may be the underlying cause for altered motivated and cognitive behaviors,” he said.

"There is this contemporary view that obesity is associated with the increased drive of the reward circuitry," Horvath added. "But here, we provide a contrasting view: that the reward aspect can be very high, but subjects can still be very lean. At the same time, it indicates that a set of people who have no interest in food, might be more prone to drug addiction."

Source: Science Daily

ScienceDaily (June 24, 2012) — Want to nail that tune that you’ve practiced and practiced? Maybe you should take a nap with the same melody playing during your sleep, new provocative Northwestern University research suggests.

Want to nail that tune that you’ve practiced and practiced? Maybe you should take a nap with the same melody playing during your sleep. (Credit: © Anton Maltsev / Fotolia)

The research grows out of exciting existing evidence that suggests that memories can be reactivated during sleep and storage of them can be strengthened in the process.

In the Northwestern study, research participants learned how to play two artificially generated musical tunes with well-timed key presses. Then while the participants took a 90-minute nap, the researchers presented one of the tunes that had been practiced, but not the other.

"Our results extend prior research by showing that external stimulation during sleep can influence a complex skill," said Ken A. Paller, professor of psychology in the Weinberg College of Arts and Sciences at Northwestern and senior author of the study.

By using EEG methods to record the brain’s electrical activity, the researchers ensured that the soft musical “cues” were presented during slow-wave sleep, a stage of sleep previously linked to cementing memories. Participants made fewer errors when pressing the keys to produce the melody that had been presented while they slept, compared to the melody not presented.

"We also found that electrophysiological signals during sleep correlated with the extent to which memory improved," said lead author James Antony of the Interdepartmental Neuroscience Program at Northwestern. "These signals may thus be measuring the brain events that produce memory improvement during sleep."

The age-old myth that you can learn a foreign language while you sleep is sure to come to mind, said Paul J. Reber, associate professor of psychology at Northwestern and a co-author of the study.

"The critical difference is that our research shows that memory is strengthened for something you’ve already learned," Reber said. "Rather than learning something new in your sleep, we’re talking about enhancing an existing memory by re-activating information recently acquired."

The researchers, he said, are now thinking about how their findings could apply to many other types of learning.

"If you were learning how to speak in a foreign language during the day, for example, and then tried to reactivate those memories during sleep, perhaps you might enhance your learning."

Paller said he hopes the study will help them learn more about the basic brain mechanisms that transpire during sleep to help preserve memory storage.

"These same mechanisms may not only allow an abundance of memories to be maintained throughout a lifetime, but they may also allow memory storage to be enriched through the generation of novel connections among memories," he said.

The study opens the door for future studies of sleep-based memory processing for many different types of motor skills, habits and behavioral dispositions, Paller said.

Source: Science Daily

ScienceDaily (June 23, 2012) — The commonly-used epilepsy drug, valproic acid (VPA), can have a highly beneficial effect on some babies born with spinal muscular atrophy (SMA), the number one genetic killer during early infancy. But in about two-thirds of such cases it is either damaging or simply has no effect. Now, for the first time, researchers have found a way to identify which patients are likely to respond well to VPA prior to starting treatment. Their results have major implications, not just for SMA patients, but for other conditions treated with the drug such as migraine and epilepsy, and may even provide the conditions for turning VPA non-responders into responders, the researchers say.

Dr. Lutz Garbes, from the Institute of Human Genetics, University of Cologne, Germany, will tell the annual conference of the European Society of Human Genetics on June 24 that he and his colleagues had analysed blood RNA samples from a small group of SMA patients who had been treated with VPA. They found, as expected, that only about one third of patients responded well. In an attempt to discover whether blood sampling was the most appropriate test method to use, they also looked at VPA response in another tissue — fibroblasts (a type of skin cell). They found that the response in blood and in skin was the same in 60% of cases.

The researchers then generated pluripotent stem cells from fibroblasts of both a VPA responder and a non-responder, and differentiated them into GABAergic neurons (neurons that produce the amino acid GABA, the chief neurotransmitter in the mammalian nervous system). These neurons, when treated with VPA, exhibited a similar response to that previously found in blood and fibroblasts.

"This indicates for the first time that response to VPA is the same among blood and skin and suggests that monitoring blood for VPA therapy is indeed feasible in central nervous system diseases," says Dr. Garbes. "But, even more importantly, by using the SMA patients’ fibroblasts we were able to identify a decisive factor in the suppression of the positive response to VPA treatment. Utilising transcriptome-wide microarray profiling*, we found that high levels of the fatty acid transporter protein CD36 are associated with the lack of positive response to treatment.

"The implications of this discovery are far-reaching. First, we have been able to prove that monitoring blood is a reliable method for doctors to determine response to VPA treatment in many central nervous system diseases, since our findings are not specific to SMA. Second, the identification of CD36 as the crucial factor in suppressing response to treatment provides a simple way of appraising whether a patient will respond to therapy before treatment starts. And third, in the long run we may find a way to target CD36 in order to be able to change a non-VPA responder into a responder."

Knowing that CD36 is a crucial factor here means that the current, potentially dangerous, ‘trial and error’ approach to VPA treatment is now obsolete, the researchers say. Screening of patients for CD36 prior to treatment would mean that only those who would respond positively to VPA would be given it. This is important because, in some cases, VPA can cause life-threatening side-effects such as impairment of liver, blood cell and pancreatic function, especially in those just starting the treatment. “But we still do not understand how CD36 suppresses response to VPA, only that it does so,” says Dr. Garbes. “A greater understanding of its effects could also lead to the detection of even better targets to overcome the problem. “

In the case of SMA, VPA works by inhibiting enzymes called histone deacetylase (HDACs) which are involved in regulating the packaging of DNA. HDACs lead to a denser DNA packaging whereby protein production from genes is reduced. Other enzymes called histone acetyltransferases (HATs) lead to a more relaxed DNA structure, producing more protein. By inhibiting HDACs with VPA, the DNA packaging balance shifts towards the more relaxed structure and thus genes get activated and proteins produced. In SMA, the crucial gene is SMN2, a copy gene of the disease-determining gene SMN1. In healthy individuals, SMN1 is the major source of SMN protein, but SMN2 cannot fully compensate for the loss of SMN1 in SMA patients. By increasing SMN2 activity, it will produce more SMN protein and ameliorate the condition.

"Avoiding needless VPA treatment of non-responders would have a major effect on healthcare costs and improve quality of life for patients," Dr. Garbes will say. "Half of the babies born with SMA will die within two years, but the other half can live to twenty or even longer, so this is an important finding for them. Our findings may also help identify patients who are candidates for VPA treatment in many other diseases of the central nervous system, some of them very common.

"In the EU, approximately 550 SMA babies are born each year, and there are about 311,000 new cases of epilepsy per year. It is estimated that, in Europe, migraine affects up to 28% of people at some time in their lives. We are happy that we may have been able to contribute to the development of personalised medicine for so many people," he will conclude.

*A transcriptome-wide microarray profile provides a way of identifying all the genes that are differentially expressed in distinct cell populations or subtypes, allowing the effects of treatment to be monitored.

Source: Science Daily

ScienceDaily (June 22, 2012) — Some dementia patients show symptoms of a malfunctioning immune system and can receive appropriate treatment.

Scientists at Charité — Universitätsmedizin Berlin have succeeded in recommending a new type of therapeutic approach to dementia. The study published in the journal Neurology shows that immune reactions against the body’s own nerve cells can be the cause of advanced dementia and an appropriate immune suppressive therapy can develop with significant effectiveness.

Dementia burdens society with high costs, and those affected by it and their family members carry a tremendous psychosocial burden. Dementia is increasingly perceived as a sword of Damocles over an aging society due to its often unclear origin, difficult prevention and unsatisfactory therapies.

Together with a workgroup and cooperation partners in Germany and the US, Dr. Harald Prüß, physician at the Klinik für Neurologie of the Charité, was able to prove that dementia is also caused by the immune system. As an accessory symptom of an autoimmune disease, dementia can thus be treated. This approach to diagnostic criteria has been overlooked until now. It was proven that a number of patients in this study who suffered from advanced memory loss had developed an immune defense response with antibodies against an ion channel in the brain, a so-called NMDA-type glutamate channel. Particular proteins in the nerve cell membrane are reduced leading to the characteristic disruption in nerve function and synapsis loss. Those affected exhibit memory problems and abnormalities in mood and emotion. Eliminating these antibodies through hemodialysis improved the symptoms in cerebral metabolism in the hippocampus region — a part of the brain that is relevant for memory performance and particularly affected by dementia.

"Through the study results, a completely new approach to diagnosing dementia can possibly result. At the moment we are working on a follow-up study with larger test groups in order to verify our approach even further," explains Harald Prüß. He adds: "The potential promise of this new approach is that completely new perspectives could result for an entire group of people suffering from dementia for whom no specific therapeutic option exists."

Source: Science Daily

ScienceDaily (June 22, 2012) — A longstanding question in brain research is how information is processed in the brain. Neuroscientists at the Charité — Universitätsmedizin Berlin, Cluster of Excellence NeuroCure and University of Newcastle have made a contribution towards answering this question. In a new study, they have shown that signals are generated not only in the cell body of nerve cells, but also in their output extension, the axon. A specific filter cell regulates signal propagation.

These findings have now been published in the journal Science.

Until now it has been assumed that information flow in nerve cells proceeds along a “one-way street.” Electrical impulses are initiated at the cell body and propagate along the axon to the next neuron, where they are received by extensions, the dendrites, acting as antennae. However, the team around Charité researchers Tengis Gloveli and Tamar Dugladze has demonstrated that this model needs to be revised. They discovered that signals can also be initiated in axons, i.e. outside the cell body. This happens during highly synchronous neuronal activity as, for example, in a state of heightened attention. Moreover, these axonally generated signals flow bidirectionally and represent a new principle of information processing: on the one hand, impulses propagate from their origin towards other nerve cells; on the other hand, the signals also backpropagate towards the cell body, i.e. in the “wrong direction” down the one-way street. A potential problem is that backpropagating signals could lead to excessive cell activation.

However, the researchers found that backpropagating signals do not reach the cell body under normal conditions. The reason for this, the scientists discovered, is a natural filter that prevents these signals from passing. “Axo-axonic cells, an inhibitory cell type, regulate signal propagation and thus occupy an outstanding strategic position,” explains Tamar Dugladze. Through the filter function, these cells allow signals initiated at the cell body to pass, but suppress backpropagating impulses generated in the axon. By this means, excessive activation of the cell body is prevented. In experiments, the scientists could show that when this filter function is deactivated, backpropagating signals are allowed to pass, resulting in higher cell activation.

These filter cells can become damaged in various neurological diseases. The consequent misregulation of signal flow, in turn, has fatal effects on information processing in the brain. “Results of this study shed new light on the central question of how signals are processed in the brain. In addition, these findings could help us better understand the development and progress of neuronal diseases such as epilepsy, which involves excessive hypersynchronous activity of large sets of neurons. This knowledge could open up new therapeutic approaches,” says Tengis Gloveli. The neuroscientists will therefore focus their future research on both basic understanding of the mechanisms of signal flow in the nervous system, and the relevance of these mechanisms in the genesis of epilepsy.

Source: Science Daily

ScienceDaily (June 22, 2012) — The gene p53 is the most commonly mutated gene in cancer. p53 is dubbed the “guardian of the genome” because it blocks cells with damaged DNA from propagating and eventually becoming cancerous. However, new research led by Ute M. Moll, M.D., Professor of Pathology at Stony Brook University School of Medicine, and colleagues, uncovers a novel role for p53 beyond cancer in the development of ischemic stroke. The research team identified an unexpected critical function of p53 in activating necrosis, an irreversible form of tissue death, triggered during oxidative stress and ischemia.

Dr. Ute Moll, Professor of Pathology, has uncovered a novel role for p53 in the development of ischemic stroke. (Credit: Image courtesy of Stony Brook Medicine)

The findings are detailed online in Cell.

Ischemia-associated oxidative damage leads to irreversible necrosis which is a major cause of catastrophic tissue loss. Elucidating its signaling mechanism is of paramount importance. p53 is a central cellular stress sensor that responds to multiple insults including oxidative stress and is known to orchestrate apoptotic and autophagic types of cell death. However, it was previously unknown whether p53 can also activate oxidative stress-induced necrosis, a regulated form of cell death that depends on the mitochondrial permeability transition pore (PTP) pore.

"We identified an unexpected and critical function of p53 in activating necrosis: In response to oxidative stress in normal healthy cells, p53 accumulates in the mitochondrial matrix and triggers the opening of the PTP pore at the inner mitochondrial membrane, leading to collapse of the electrochemical gradient and cell necrosis," explains Dr. Moll. "p53 acts via physical interaction with the critical PTP regulator Cyclophylin D (CypD). This p53 action occurs in cultured cells and in ischemic stroke in mice. "

Of note, they found in their model that when the destructive p53-CypD complex is blocked from forming by using Cyclosporine-A type inhibitors, the brain tissue is strongly protected from necrosis and stroke is prevented.

"The findings fundamentally expand our understanding of p53-mediated cell death networks," says Dr. Moll. "The data also suggest that acute temporary blockade of the destructive p53-CypD complex with clinically well-tolerated Cyclosporine A-type inhibitors may lead to a therapeutic strategy to limit the extent of an ischemic stroke in patients."

"p53 is one of the most important genes in cancer and by far the most studied," says Yusuf A. Hannun, M.D., Director of the Stony Brook University Cancer Center, Vice Dean for Cancer Medicine, and the Joel Kenny Professor of Medicine at Stony Brook. "Therefore, this discovery by Dr. Moll and her colleagues in defining the mechanism of a new p53 function and its importance in necrotic injury and stoke is truly spectacular."

Dr. Moll has studied p53 for 20 years in her Stony Brook laboratory. Her research has led to numerous discoveries about the function of p53 and two related genes. For example, previous to this latest finding regarding p53 and stroke, Dr. Moll identified that p73, a cousin to p53, steps in as a tumor suppressor gene when p53 is lost and can stabilize the genome. She found that p73 plays a major developmental role in maintaining the neural stem cell pool during brain formation and adult learning. Her work also helped to identify that another p53 cousin, called p63, has a critical surveillance function in the male germ line and likely contributed to the evolution of humans and great apes, enabling their long reproductive periods.

Source: Science Daily

ScienceDaily (June 22, 2012) — Scientists have discovered that plant compounds from a South African flower may in time be used to treat diseases originating in the brain — including depression. At the University of Copenhagen, a number of these substances have now been tested in a laboratory model of the blood-brain barrier.

Crinum from South Africa. (Credit: Gary I. Stafford)

Scientists at the University of Copenhagen have previously documented that substances from the South African plant species Crinum and Cyrtanthus — akin to snowdrops and daffodils — have an effect on the mechanisms in the brain that are involved in depression. This research has now yielded further results, since a team based at the Faculty of Health and Medical Sciences has recently shown how several South African daffodils contain plant compounds whose characteristics enable them to negotiate the defensive blood-brain barrier that is a key challenge in all new drug development.

"Several of our plant compounds can probably be smuggled past the brain’s effective barrier proteins. We examined various compounds for their influence on the transporter proteins in the brain. This study was made in a genetically-modified cell model of the blood-brain barrier that contains high levels of the transporter P-glycoprotein. Our results are promising, and several of the chemical compounds studied should therefore be tested further, as candidates for long-term drug development," says Associate Professor Birger Brodin.

"The biggest challenge in medical treatment of diseases of the brain is that the drug cannot pass through the blood-brain barrier. The blood vessels of the brain are impenetrable for most compounds, one reason being the very active transporter proteins. You could say that the proteins pump the drugs out of the cells just as quickly as they are pumped in. So it is of great interest to find compounds that manage to ‘trick’ this line of defence."

The results of the study have been published in the Journal of Pharmacy and Pharmacology.

It will nonetheless be a long time before any possible new drug reaches our pharmacy shelves: “This is the first stage of a lengthy process, so it will take some time before we can determine which of the plant compounds can be used in further drug development,” says Birger Brodin.

Yet this does not curb his enthusiasm for the opportunities from the interdisciplinary cooperation with organic scientists from the Department of Drug Design and Pharmacology and the Natural History Museum of Denmark.

"In my research group, we have had a long-term focus on the body’s barrier tissue — and in recent years particularly the transport of drug compounds across the blood-brain barrier. More than 90 per cent of all potential drugs fail the test by not making it through the barrier, or being pumped out as soon as they do get in. Studies of natural therapies are a valuable source of inspiration, giving us knowledge that can also be used in other contexts," Birger Brodin emphasises.

Source: Science Daily

June 22, 2012 By Virat Markandeya

Listening to a single voice in a crowded cocktail party sometimes seems like picking a needle out of a haystack, but new research shows that people may be better at this than expected.

New research shows that people can comprehend one sound among many.

The results surprised the University of Washington, Seattle, research team, which tested how well people could pick out one sound from a dense collection of noises.

The researchers asked ten subjects to listen to multiple streams of letters. A stream consisted of a repeating letter, for example, Q-Q-Q-Q. If four streams were played, the listener heard four different repeating letters, say, D, C, Q and J. The letters came fast —the time interval between each letter was just one-twelfth of a second.

In front of the listener was a computer screen. Before the start of each trial, the researchers put one of the four letters on the screen to prime the subject to focus on it. If he heard an oddball letter in that stream, such as R instead of Q, he was to press a button.

To make it easier on the listener, each letter stream carried a different pitch and came from a different location in the room. R was chosen as the oddball because it doesn’t rhyme with any other letter.  

"Unlike most experiments where you try to make it difficult for the listener to do the task, we tried to give every advantage we could," said Adrian K.C. Lee, a speech and hearing researcher at the university, who worked closely with Ross Maddox.

As expected, when the number of streams went up, the ability to discern the letter came down. But even with 12 streams the letter was identified correctly around 70 percent of the time.

"We expected that 12 streams would have broken the upper limits of the [subject’s hearing] system," said Lee. "It is surprising that even with twelve things coming at you at the same time you can lock on to one with reasonably high accuracy."

The work was presented last month at the Acoustics 2012 Hong Kong conference.

Down the line, the researchers want to use these experiments to design a way for paralyzed patients to control a wheelchair or a computer using brain signals. Such devices, called brain-computer interfaces, have mostly relied on visual or motor stimuli. Typically, a subject might focus on a visual cue or imagine making a movement. Using a machine that detects brain signals, such as an electroencephalogram, researchers would attempt to characterize the brain responses connected with that task and translate them into commands. Focusing on an auditory signal too produces brain signals that can be characterized. However, the current study did not look at brain signals.

A very practical reason to look at auditory interfaces is that eye-gaze control — on which visually-controlled interfaces are based — is often absent in people in a late stage of a neurodegenerative disease, said Martijn Schreuder, a researcher at the Berlin Institute of Technology.

Schreuder, who has worked on an interface where subjects spelled words by focusing on particular sounds, pointed out that auditory interfaces allow someone who is completely blind to communicate.

Schreuder said Lee’s work provides hints on “whether or not it’s good or bad to have different [audio] streams or whether it is good to have a quicker repetition or not.” To his knowledge, this is the first time researchers have gone up to 12 streams. Previous research included only two streams.

The other part Schreuder found interesting was how quickly the listeners learned how to discriminate between letter streams.

"There is a difference between being able to spell one letter every two minutes or spelling three letters per minute, which is the range [brain-computer interfaces] go," Schreuder said. "So if one selection takes 20 seconds, it’s worse than if it goes 10 seconds."

The University of Washington researchers are planning follow-up experiments to directly investigate how the brain responds to audio streams.

Provided by Inside Science News Service

Source: medicalxpress.com