Brain tumour cells killed by anti-nausea drug

New research from the University of Adelaide has shown for the first time that the growth of brain tumours can be halted by a drug currently being used to help patients recover from the side effects of chemotherapy.

The discovery has been made during a study looking at the relationship between brain tumours and a peptide associated with inflammation in the brain, called “substance P”.

Substance P is commonly released throughout the body by the nervous system, and contributes to tissue swelling following injury. In the brain, levels of substance P greatly increase after traumatic brain injury and stroke.

"Researchers have known for some time that levels of substance P are also greatly increased in different tumour types around the body," says Dr Elizabeth Harford-Wright, a postdoctoral fellow in the University’s Adelaide Centre for Neuroscience Research.

"We wanted to know if these elevated levels of the peptide were also present in brain tumour cells, and if so, whether or not they were affecting tumour growth. Importantly, we wanted to see if we could stop tumour growth by blocking substance P."

Dr Harford-Wright found that levels of substance P were greatly increased in brain tumour tissue.

Knowing that substance P binds to a receptor called NK1, Dr Harford-Wright used an antagonist drug called Emend® to stop substance P binding to the receptor. Emend® is already used in cancer clinics to help patients with chemotherapy-induced nausea.

The results were startling.

"We were successful in blocking substance P from binding to the NK1 receptor, which resulted in a reduction in brain tumour growth - and it also caused cell death in the tumour cells," Dr Harford-Wright says.

"So preventing the actions of substance P from carrying out its role in brain tumours actually halted the growth of brain cancer.

"This is a very exciting result, and it offers further opportunities to study possible brain tumour treatments over the coming years."

Researchers find that alcohol consumption damages brain’s support cells

Alcohol consumption affects the brain in multiple ways, ranging from acute changes in behavior to permanent molecular and functional alterations. The general consensus is that in the brain, alcohol targets mainly neurons. However, recent research suggests that other cells of the brain known as astrocytic glial cells or astrocytes are necessary for the rewarding effects of alcohol and the development of alcohol tolerance. The study, first-authored by Dr. Leonardo Pignataro, was published in the February 6th issue of the scientific journal Brain and Behavior.

"This is a fascinating result that we could have never anticipated. We know that astrocytes are the most abundant cell type in the central nervous system and that they are crucial for neuronal growth and survival, but so far, these cells had been thought to be involved only in brain’s support functions. Our results, however, show that astrocytes have an active role in alcohol tolerance and dependence," explains Dr. Pignataro.

The team of researchers from Columbia and Yale Universities analyzed how alcohol exposure changes gene expression in astrocyte cells and identified gene sets associated with stress, immune response, cell death, and lipid metabolism, which may have profound implications for normal neuronal activity in the brain. “Our findings may explain many of the long-term inflammatory and degenerative effects observed in the brain of alcoholics,” says Dr. Pignataro. “The change in gene expression observed in alcohol-exposed astrocytes supports the idea that some of the alcohol consumed reaches the brain and that ethanol (the active component of alcoholic beverages) is locally metabolized, increasing the production free radicals that react with cell components to affect the normal function of cells. This activates a cellular stress response in the cells in an attempt to defend from this chemical damage. On the other hand, the body recognizes these oxidized molecules as “foreign objects” generating an immune response against them that leads to the death of damage cells. This mechanism can explain the inflammatory degenerative process observed in the brain of chronic alcoholics, allowing for the development of different and novel therapeutically approaches to treat this disease” added Dr. Pignataro.

The consequences of alcohol on astrocytes revealed in this study go far beyond what happens to this particular cell type. Astrocytes play a crucial role in the CNS, supporting normal neuronal activity by maintaining homeostasis. Therefore, alcohol changes in gene expression in astrocytes may have profound implications for neuronal activity in the brain.

These findings will help scientists better understand alcohol-associated disorders, such as the brain neurodegenerative damage associated with chronic alcoholism and alcohol tolerance and dependence. “We hope that this newly discovered role of astrocytes will give scientists new targets other than neurons to develop novel therapies to treat alcoholism,” Leonardo Pignataro concluded.

Difficulty in Recognizing Faces in Autism Linked to Performance in a Group of Neurons

Neuroscientists at Georgetown University Medical Center (GUMC) have discovered a brain anomaly that explains why some people diagnosed with autism cannot easily recognize faces — a deficit linked to the impairments in social interactions considered to be the hallmark of the disorder.

They also say that the novel neuroimaging analysis technique they developed to arrive at this finding is likely to help link behavioral deficits to differences at the neural level in a range of neurological disorders.

The final manuscript published March 15 in the online journal NeuroImage: Clinical, the scientists say that in the brains of many individuals with autism, neurons in the brain area that processes faces (the fusiform face area, or FFA) are too broadly “tuned” to finely discriminate between facial features of different people. They made this discovery using a form of functional magnetic resonance imaging (fMRI) that scans output from the blueberry-sized FFA, located behind the right ear.

“When your brain is processing faces, you want neurons to respond selectively so that each is picking up a different aspect of individual faces. The neurons need to be finely tuned to understand what is dissimilar from one face to another,” says the study’s senior investigator, Maximilian Riesenhuber, PhD, an associate professor of neuroscience at GUMC.

“What we found in our 15 adult participants with autism is that in those with more severe behavioral deficits, the neurons are more broadly tuned, so that one face looks more like another, as compared with the fine tuning seen in the FFA of typical adults,” he says.

“And we found evidence that reduced selectivity in FFA neurons corresponded to greater behavioral deficits in everyday face recognition in our participants. This makes sense. If your neurons cannot tell different faces apart, it makes it more difficult to tell who is talking to you or understand the facial expressions that are conveyed, which limits social interaction.”

Riesenhuber adds that there is huge variation in the ability of individuals diagnosed with autism to discriminate faces, and that some autistic people have no problem with facial recognition.

“But for those that do have this challenge, it can have substantial ramifications — some researchers believe deficits in face processing are at the root of social dysfunction in autism,” he says.

The neural basis for face processing

Neuroscientists have used traditional fMRI studies in the past to probe the neural bases of behavioral differences in people with autism, but these studies have produced conflicting results, says Riesenhuber.  “The fundamental problem with traditional fMRI techniques is that they can tell which parts of the brain become active during face processing, but they are poor at directly measuring neuronal selectivity,” he says, “and it is this neuronal selectivity that predicts face processing performance, as shown in our previous studies.”

To test their hypothesis that differences in neuronal selectivity in the FFA are foundational to differences in face processing abilities in autism, Riesenhuber and the study’s lead author, neuroscientist Xiong Jiang, PhD, developed a novel brain imaging analysis technique, termed local regional heterogeneity, to estimate neuronal selectivity.

“Local regional heterogeneity, or Hcorr, as we called it, is based on the idea that neurons that have similar selectivities will on average show similar responses, whereas neurons that like different stimuli will respond differently,” says Jiang. “This means that individuals with face processing deficits should show more homogeneous activity in their FFA than individuals with more typical face recognition abilities.”

They tested the method in 15 adults with autism and 15 adults without the disorder. The autistic participants also underwent a standard assessment of social/behavioral functioning.

The researchers found that in each autistic participant, behavioral ability to tell faces apart was tightly linked to levels of tuning specificity in the right FFA as estimated with Hcorr. This finding was confirmed by another advanced imaging technique, fMRI rapid adaptation, shown by the group in previous work to be a good estimator of neuronal selectivity.

“Compared to the more well-established fMRI-rapid adaptation technique, Hcorr has several significant advantages,” says Jiang. “Hcorr is more sensitive and can estimate neuronal selectivity as well as fMRI rapid adaptation, but with much shorter scans, and Hcorr can even estimate neuronal selectivity using data from resting state scans, thus making the technique suitable even for individuals that cannot perform complicated tasks in the scanner, such as low-functioning autistic adults, or young children.”

“The study suggests that, just as in typical adults, the FFA remains the key region responsible for face processing and that changes in neuronal selectivity in this area are foundational to the variability in face processing abilities found in autism. Our study identifies a clear target for intervention,” says Riesenhuber. Indeed, after the study was completed, the researchers successfully attempted to improve facial recognition skills in an autistic participant. They showed the participant pairs of faces that were very dissimilar at first, but became increasingly similar, and found that FFA tuning improved along with behavioral ability to tell the faces apart. “This suggests high-level brain areas may still be somewhat plastic in adulthood,” says Riesenhuber.

AAN Issues Updated Sports Concussion Guideline: Athletes with Suspected Concussion Should Be Removed from Play

With more than one million athletes now experiencing a concussion each year in the United States, the American Academy of Neurology (AAN) has released an evidence-based guideline for evaluating and managing athletes with concussion. This new guideline replaces the 1997 AAN guideline on the same topic. The new guideline is published in the March 18, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology, was developed through an objective evidence-based review of the literature by a multidisciplinary committee of experts and has been endorsed by a broad range of athletic, medical and patient groups.

“Among the most important recommendations the Academy is making is that any athlete suspected of experiencing a concussion immediately be removed from play,” said co-lead guideline author Christopher C. Giza, MD, with the David Geffen School of Medicine and Mattel Children’s Hospital at UCLA and a member of the AAN. “We’ve moved away from the concussion grading systems we first established in 1997 and are now recommending concussion and return to play be assessed in each athlete individually. There is no set timeline for safe return to play.”

The updated guideline recommends athletes with suspected concussion be immediately taken out of the game and not returned until assessed by a licensed health care professional trained in concussion, return to play slowly and only after all acute symptoms are gone. Athletes of high school age and younger with a concussion should be managed more conservatively in regard to return to play, as evidence shows that they take longer to recover than college athletes.

The guideline was developed reviewing all available evidence published through June 2012. These practice recommendations are based on an evaluation of the best available research. In recognition that scientific study and clinical care for sports concussions involves multiple specialties, a broad range of expertise was incorporated in the author panel. To develop this document, the authors spent thousands of work hours locating and analyzing scientific studies. The authors excluded studies that did not provide enough evidence to make recommendations, such as reports on individual patients or expert opinion. At least two authors independently analyzed and graded each study.

According to the guideline:

• Among the sports in the studies evaluated, risk of concussion is greatest in football and rugby, followed by hockey and soccer. The risk of concussion for young women and girls is greatest in soccer and basketball.

• An athlete who has a history of one or more concussions is at greater risk for being diagnosed with another concussion.

• The first 10 days after a concussion appears to be the period of greatest risk for being diagnosed with another concussion.

• There is no clear evidence that one type of football helmet can better protect against concussion over another kind of helmet. Helmets should fit properly and be well maintained.

• Licensed health professionals trained in treating concussion should look for ongoing symptoms (especially headache and fogginess), history of concussions and younger age in the athlete. Each of these factors has been linked to a longer recovery after a concussion.

• Risk factors linked to chronic neurobehavioral impairment in professional athletes include prior concussion, longer exposure to the sport and having the ApoE4 gene.

• Concussion is a clinical diagnosis. Symptom checklists, the Standardized Assessment of Concussion (SAC), neuropsychological testing (paper-and-pencil and computerized) and the Balance Error Scoring System may be helpful tools in diagnosing and managing concussions but should not be used alone for making a diagnosis.

Signs and symptoms of a concussion include:

Headache and sensitivity to light and sound Changes to reaction time, balance and coordination Changes in memory, judgment, speech and sleep Loss of consciousness or a “blackout” (happens in less than 10 percent of cases)

“If in doubt, sit it out,” said Jeffrey S. Kutcher, MD, with the University of Michigan Medical School in Ann Arbor and a member of the AAN. “Being seen by a trained professional is extremely important after a concussion. If headaches or other symptoms return with the start of exercise, stop the activity and consult a doctor. You only get one brain; treat it well.”

The guideline states that while an athlete should immediately be removed from play following a concussion, there is currently insufficient evidence to support absolute rest after concussion. Activities that do not worsen symptoms and do not pose a risk of repeat concussion may be part of concussion management.

The guideline is endorsed by the National Football League Players Association, the American Football Coaches Association, the Child Neurology Society, the National Association of Emergency Medical Service Physicians, the National Academy of Neuropsychology, the National Association of School Psychologists, the National Athletic Trainers Association and the Neurocritical Care Society.

Hypertension Could Bring Increased Risk for Alzheimer’s disease

A study in the Journal of the American Medical Association Neurology suggests that controlling or preventing risk factors, such as hypertension, earlier in life may limit or delay the brain changes associated with Alzheimer’s disease and other age-related neurological deterioration.

Dr. Karen Rodrigue, assistant professor in the UT Dallas Center for Vital Longevity (CVL), was lead author of a study that looked at whether people with both hypertension and a common gene had more buildup of a brain plaque called amyloid protein, which is associated with Alzheimer’s disease. Scientists believe amyloid is the first symptom of Alzheimer’s disease and shows up a decade or more before symptoms of memory impairment and other cognitive difficulties begin. The gene, known as APOE 4, is carried by 20 percent of the population.

Until recently, amyloid plaque could be seen only at autopsy, but new brain scanning techniques allow scientists to see plaque in living brains of healthy adults. Findings from both autopsy and amyloid brain scans show that at least 20 percent of typical older adults carry elevated levels of amyloid, a substance made up mostly of protein that is deposited in organs and tissues.

“I became interested in whether hypertension was related to increased risk of amyloid plaques in the brains of otherwise healthy people,” Rodrigue said. “Identifying the most significant risk factors for amyloid deposition in seemingly healthy adults will be critical in advancing medical efforts aimed at prevention and early detection.”

Based on evidence that hypertension was associated with Alzheimer’s disease, Rodrigue suspected that the combination of hypertension and the presence of the APOE-e4 gene might lead to particularly high levels of amyloid plaque in healthy adults.

Depression stems from miscommunication between brain cells

A new study from the University of Maryland School of Medicine suggests that depression results from a disturbance in the ability of brain cells to communicate with each other. The study indicates a major shift in our understanding of how depression is caused and how it should be treated. Instead of focusing on the levels of hormone-like chemicals in the brain, such as serotonin, the scientists found that the transmission of excitatory signals between cells becomes abnormal in depression. The research, by senior author Scott M. Thompson, Ph.D., Professor and Interim Chair of the Department of Physiology at the University of Maryland School of Medicine, was published online in the March 17 issue of Nature Neuroscience.

"Dr. Thompson’s groundbreaking research could alter the field of psychiatric medicine, changing how we understand the crippling public health problem of depression and other mental illness," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs at the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor and Dean at the University of Maryland School of Medicine. "This is the type of cutting-edge science that we strive toward at the University of Maryland, where discoveries made in the laboratory can impact the clinical practice of medicine."

The first major finding of the study was the discovery that serotonin has a previously unknown ability to strengthen the communication between brain cells. “Like speaking louder to your companion at a noisy cocktail party, serotonin amplifies excitatory interactions in brain regions important for emotional and cognitive function and apparently helps to make sure that crucial conversations between neurons get heard,” says Dr. Thompson. “Then we asked, does this action of serotonin play any role in the therapeutic action of drugs like Prozac?”

To understand what might be wrong in the brains of patients with depression and how elevating serotonin might relieve their symptoms, the study team examined the brains of rats and mice that had been repeatedly exposed to various mildly stressful conditions, comparable to the types of psychological stressors that can trigger depression in people.

The researchers could tell that their animals became depressed because they lost their preference for things that are normally pleasurable. For example, normal animals given a choice of drinking plain water or sugar water strongly prefer the sugary solution. Study animals exposed to repeated stress, however, lost their preference for the sugar water, indicating that they no longer found it rewarding. This depression-like behavior strongly mimics one hallmark of human depression, called anhedonia, in which patients no longer feel rewarded by the pleasures of a nice meal or a good movie, the love of their friends and family, and countless other daily interactions.

A comparison of the activity of the animals’ brain cells in normal and stressed rats revealed that stress had no effect on the levels of serotonin in the ‘depressed’ brains. Instead, it was the excitatory connections that responded to serotonin in strikingly different manner. These changes could be reversed by treating the stressed animals with antidepressants until their normal behavior was restored.

"In the depressed brain, serotonin appears to be trying hard to amplify that cocktail party conversation, but the message still doesn’t get through," says Dr. Thompson. Using specially engineered mice created by collaborators at Johns Hopkins University School of Medicine, the study also revealed that the ability of serotonin to strengthen excitatory connections was required for drugs like antidepressants to work.

Sustained enhancement of communication between brain cells is considered one of the major processes underlying memory and learning. The team’s observations that excitatory brain cell function is altered in models of depression could explain why people with depression often have difficulty concentrating, remembering details, or making decisions. Additionally, the findings suggest that the search for new and better antidepressant compounds should be shifted from drugs that elevate serotonin to drugs that strengthen excitatory connections.

"Although more work is needed, we believe that a malfunction of excitatory connections is fundamental to the origins of depression and that restoring normal communication in the brain, something that serotonin apparently does in successfully treated patients, is critical to relieving the symptoms of this devastating disease," Dr. Thompson explains.

(Image: McGovern Institute, MIT)

Brainless robots swarm just like animals

Swarming patterns and herding behaviours have been observed throughout the animal kingdom. Scientists and mathematicians have pondered the cause of complex relationships and group dynamics at work that allow schools of fish, such as herring, and flocks of birds, such as starlings, to move together in apparent unity — and now, in an interesting twist to the discussion, a team of engineers from Harvard University has observed apparent collective behaviour in brainless robots.

The robot research team was looking for a way to investigate the transition that swarming groups make from random behaviour into collective motion. In order to observe a randomly moving collective, they built the simplest of “self-propelled automatons”, the charmingly named Bristle-Bot (BBots).

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Brave New Machines

Robots are here to stay. They will be smarter, more versatile, more autonomous, and more like us in many ways. We humans will need to adapt to keep up.

The word “robot” was used for the first time only about 80 years ago, in the play “RUR” by the Czech author Karel Capek. The robots in that book were artificial humans, chemically synthesized using appropriate formulas. Robots at present and in the future will be made largely of inorganic materials, both mechanical and electronic. However, some form of hybridization between electromechanical and biological subsystems is possible and will occur. I believe that the major developments in robotics in the next 100 years will be the following areas:

Robot intelligence: The ability of a robot to solve problems, to learn, to interact with humans and other robots, and related skills are all measures of intelligence. Robots will indeed be increasingly intelligent, because:

- High speed memory, long term storage capacity, and speed of the on-board computers will continue to increase. Futurist Ray Kurzweil has predicted that the capacity of robot brains will exceed that of human brains within the next 20 years.

- Neuroscience is rapidly obtaining better and better models of the information processing ability of the human brain. These models will lead to the development of software to enable robot brains to emulate more and more of the features of the human brain.

- Research in learning will enable robots to learn by imitating humans, from their own mistakes and from their successes.

Human-robot interaction: This is an area of significant research activity at the present time. I believe that during the coming decades robots will be able to interact with humans (and with each other) in increasingly human-like ways, including speech and gestures. Robots will be able to understand the semantic as well as the emotional aspects of speech, so that they will understand the significance of increasing loudness, irritation, affection, and other emotional aspects in spoken utterances, and they will be able to include these aspects in their own speech as well.

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