Neuroscience

A new study suggests that colds and other minor infections may temporarily increase stroke risk in children. The study found that the risk of stroke was increased only within a three-day period between a child’s visit to the doctor for signs of infection and having the stroke.

The study was led by researchers at UCSF Benioff Children’s Hospital San Francisco in collaboration with the Kaiser Permanente Division of Research.

“These findings suggest that infection has a powerful but short-lived effect on stroke risk,” said senior author Heather Fullerton, MD, a pediatric vascular neurologist and medical director of the Pediatric Brain Center at UCSF Benioff Children’s Hospital San Francisco.

“We’ve seen this increase in stroke risk from infection in adults, but until now, an association has not been studied in children.”

Strokes are extremely rare in children, affecting just five out of 100,000 kids per year. “The infections are acting as a trigger in children who are likely predisposed to stroke,” said Fullerton. “Infection prevention is key for kids who are at risk for stroke, and we should make sure those kids are getting vaccinated against whatever infections – such as flu - that they can.”

The study appears in the August 20, 2014, online issue of Neurology.

In the study, researchers reviewed a Kaiser Permanente database of 2.5 million children and identified 102 children who had an ischemic stroke – a stroke that occurs as a result of an obstruction within a blood vessel supplying blood to the brain - without a major infection such as meningitis or sepsis. The researchers then compared them with 306 children without stroke. Medical records for the group of children who had a stroke were reviewed for minor infections up to two years before their strokes.

The study found that the risk of stroke was increased only within a three-day time frame, which the researchers say represents a period of acute inflammation. As an infection resolves, the inflammation decreases, as does the stroke risk.

A total of 10 of the 102 children who had a stroke had a doctor visit for an infection within three days of the stroke, or 9.8 percent, while only two of the 306 control participants, or 0.7 percent, had an infection during the same time period.

The children who had strokes were 12 times more likely to have had an infection within the previous three days than the children without strokes. The total number of infections over a two-year period was not associated with increased stroke risk. About 80 percent of the minor infections identified by the researchers were upper respiratory.

“It’s important the public does the things we can to prevent infection, like vaccinations, good hand washing and covering your mouth when you sneeze in order to protect all children, but it’s especially important to help prevent stroke in someone who is otherwise predisposed,” said Fullerton.

Scientists at Virginia Tech’s Virginia Bioinformatics Institute working with the Center for Cancer and Blood Disorders at Children’s National Medical Center have found a new way to diagnose brain cancer based on genetic markers found in “junk DNA.” 

The finding, recently published in Oncotarget, could revolutionize the way doctors treat certain brain cancers.

Brain cancer is the second leading cancer-related cause of death in children. Overall, 70,000 new patients were diagnosed with primary brain tumors in 2013, according to the American Brain Tumor Association. 

However, only about a third turn out to be malignant. Ordinarily, when a patient shows symptoms of a brain tumor, an MRI is performed to locate tumors, but it cannot determine whether the tumor is benign or malignant, often necessitating costly and occasionally dangerous or inconclusive biopsies. 

A simple blood test to detect genetic markers could change all that.

"Patients with less aggressive types of cancer as determined by this test would not need a biopsy," said Harold ‘Skip’ Garner, a professor and director of the Medical Informatics and Systems Division at the Virginia Bioinformatics Institute. "The biopsy is expensive both medically and financially — one percent of patients die and seven percent have permanent neurological damage from the procedure, according to the Canadian Journal of Neurology. This finding may reduce costs and save lives."

Microsatellites, long dismissed as “junk DNA,” comprise the one million DNA sequence repeats in the human genome. 

Though they’ve been effective in identifying rare conditions such as Huntington’s and Fragile X syndrome, next-generation genome sequencing is allowing researchers to find increasingly more markers for a variety of diseases, including cancer and autism. 

The study analyzed germline (blood) sequences from the National Institutes of Health 1000 Genomes Project and the Cancer Genome Atlas. 

Analyzing the microsatellites from these sequences revealed that patients with various stages of glioma showed recognizable and consistent markers in their genomes for the disease. 

This information indicates it is possible to develop a simple blood test that would help identify patients with different brain cancer grades, which could reduce invasive and inconclusive brain biopsies. 

These new, microsatellite-based diagnostics are applicable to many other cancers and diseases. It is hoped that with continued study, more markers and potential drug targets or therapies will be found. 

To further the development of such diagnostics, Garner has founded Genomeon, which holds an exclusive license in microsatellite technologies worldwide. Michael B. Waitzkin, CEO of Genomeon, said, “A blood test that can reliably differentiate between a malignant and benign brain tumor will have important clinical significance potentially preventing unnecessary brain biopsies which carry great risks to the patient and substantial costs to the health care system.”

In contrast to evidence that the amygdala stimulates stress responses in adults, researchers at Yerkes National Primate Research Center, Emory University have found that the amygdala has an inhibitory effect on stress hormones during the early development of nonhuman primates.

The results are published this week in Journal of Neuroscience.

The amygdala is a region of the brain known to be important for responses to threatening situations and learning about threats. Alterations in the amygdala have been reported in psychiatric disorders such as depression, anxiety disorders like PTSD, schizophrenia and autism spectrum disorder. However, much of what is known about the amygdala comes from research on adults.

"Our findings fit into an emerging theme in neuroscience research: that during childhood, there is a switch in amygdala function and connectivity with other brain regions, particularly the prefrontal cortex,” says Mar Sanchez, PhD, neuroscience researcher at Yerkes and associate professor of psychiatry and behavioral sciences at Emory University School of Medicine. The first author of the paper is postdoctoral fellow Jessica Raper, PhD.

The findings are part of a larger longitudinal study at Yerkes National Primate Research Center, examining how amygdala damage within the first month of life affects the development of social and emotional behaviors and neuroendocrine systems in rhesus monkeys from infancy through adulthood. The laboratories of Sanchez and Yerkes researchers Jocelyne Bachevalier, PhD and Kim Wallen, PhD are collaborating on this project.

Previous investigations at Yerkes found that as infants, monkeys with amygdala damage showed higher levels of the stress hormone cortisol. This surprising result contrasted with previous research on adults, which showed that amygdala damage results in lower levels of cortisol.

The team hypothesized that damage to the amygdala generated changes in the HPA axis: a network of endocrine interactions between the hypothalamus within the brain, the pituitary and the adrenal glands, critical for reactions to stress.

"We wanted to examine whether the alterations in stress hormones seen during infancy persisted, and what brain changes were responsible for them," Sanchez says. "In studies of adults, the amygdala and its connections are fully formed at the time of the manipulation, but here neither the amygdala or its connections were fully matured when the damage occurred."

In the current paper, the authors demonstrated that in contrast with adult animals with amygdala damage, juvenile monkeys with early amygdala damage had increased levels of cortisol in the blood, compared to controls. In their cerebrospinal fluid, they also had elevated levels of corticotropin releasing factor (CRF), the neuropeptide that initiates the stress response in the brain. Elevated CRF and cortisol are linked to anxiety and emotional dysregulation in patients with mood disorders.

Despite the increased levels of stress hormones, monkeys with early amygdala damage exhibit a blunted emotional reactivity to threats, including decreased fear and aggression, and reduced anxiety in response to stress. Still, monkeys with neonatal amygdala damage remain competent in interacting with others in their large social groups. These findings are consistent with reports of human patients with damage to the amygdala, Raper says.

"We speculate that the rich social environment provided to the monkeys promotes compensatory mechanisms in cortical regions implicated in the regulation of social behavior," she says. "But neonatal amygdala damage seems more detrimental for the development of stress neuroendocrine circuits in other areas of the brain."

The investigators plan to follow the animals into adulthood to investigate the long-term effects of early amygdala damage on stress hormones, behavior and physiological systems possibly affected by chronically high cortisol levels, such as immune, growth and reproductive functions.

The area of the brain involved in multitasking and ways to train it have been identified by a research team at the IUGM Institut universitaire de gériatrie de Montréal and the University of Montreal. The research includes a model to better predict the effectiveness of this training. Cooking while having a conversation, watching a movie while browsing the Web, or driving while listening to a radio show – multitasking is an essential skill in our daily lives. Unfortunately, it decreases with age, which makes it harder for seniors to keep up, causes them stress, and decreases their confidence. Many commercial software applications promise to improve this ability through exercises. But are these exercises truly effective, and how do they work on the brain? The team addresses these issues in two papers published in AGE and PLOS ONE.

Targeted Action for a Specific Result

The findings are important because they may help scientists develop better targeted cognitive stimulation programs or improve existing training programs. Specialists sometimes question the usefulness of exercises that may be ineffective simply because they are poorly structured. “To improve your cardiovascular fitness, most people know you need to run laps on the track and not work on your flexibility. But the way targeted training correlates to cognition has been a mystery for a long time. Our work shows that there is also an association between the type of cognitive training performed and the resulting effect. This is true for healthy seniors who want to improve their attention or memory and is particularly important for patients who suffer from damage in specific areas of the brain. We therefore need to better understand the ways to activate certain areas of the brain and target this action to get specific results,” explained Sylvie Belleville, who led the research.

Researchers are now better able to map these effects on the functioning of very specific areas of the brain. Will we eventually be able to adapt the structure of our brains through highly targeted training? “We have a long road ahead to get to that point, and we don’t know for sure if that would indeed be a desirable outcome. However, our research findings can be used right away to improve the daily lives of aging adults as well as people who suffer from brain damage,” Dr. Belleville said.

The Right Combination of Plasticity and Attentional Control

In one of the studies, 48 seniors were randomly allocated to training that either worked on plasticity and attentional control or only involved simple practice. The researchers used functional magnetic resonance imaging to evaluate the impact of this training on various types of attentional tasks and on brain function. The team showed that training on plasticity and attentional control helped the participants develop their ability to multitask. However, performing two tasks simultaneously was not what improved this skill. For the exercises, the research participants instead had to modulate the amount of attention given to each task. They were first asked to devote 80% of their attention to task A and 20% to task B and then change the ratio to 50:50 or 20:80. This training was the only type that increased functioning in the middle prefrontal region, or the area known to be responsible for multitasking abilities and whose activation decreases with age. The researchers used this data to create a predictive model of the effects of cognitive training on the brain based on the subjects’ characteristics.

Spontaneous gesture can help children learn, whether they use a spoken language or sign language, according to a new report.

Previous research by Susan Goldin-Meadow, the Beardsley Ruml Distinguished Service Professor in the Department of Psychology, has found that gesture helps children develop their language, learning and cognitive skills. As one of the nation’s leading authorities on language learning and gesture, she has also studied how using gesture helps older children improve their mathematical skills.

Goldin-Meadow’s new study examines how gesturing contributes to language learning in hearing and in deaf children. She concludes that gesture is a flexible way of communicating, one that can work with language to communicate or, if necessary, can itself become language. The article is published online by Philosophical Transactions of the Royal Society B and will appear in the Sept. 19 print issue of the journal, which is a theme issue on “Language as a Multimodal Phenomenon.”

“Children who can hear use gesture along with speech to communicate as they acquire spoken language, “Goldin-Meadow said. “Those gesture-plus-word combinations precede and predict the acquisition of word combinations that convey the same notions. The findings make it clear that children have an understanding of these notions before they are able to express them in speech.”

In addition to children who learned spoken languages, Goldin-Meadow studied children who learned sign language from their parents. She found that they too use gestures as they use American Sign Language. These gestures predict learning, just like the gestures that accompany speech.

Finally, Goldin-Meadow looked at deaf children whose hearing losses prevented them from learning spoken language, and whose hearing parents had not presented them with conventional sign language. These children use homemade gesture systems, called homesign, to communicate. Homesign shares properties in common with natural languages but is not a full-blown language, perhaps because the children lack “a community of communication partners,” Goldin-Meadow writes. Nevertheless, homesign can be the “first step toward an established sign language.” In Nicaragua, individual gesture systems blossomed into a more complex, shared system when homesigners were brought together for the first time.

These findings provide insight into gesture’s contribution to learning. Gesture plays a role in learning for signers even though it is in the same modality as sign. As a result, gesture cannot aid learners simply by providing a second modality. Rather, gesture adds imagery to the categorical distinctions that form the core of both spoken and sign languages.

Goldin-Meadow concludes that gesture can be the basis for a self-made language, assuming linguistic forms and functions when other vehicles are not available. But when a conventional spoken or sign language is present, gesture works along with language, helping to promote learning.

Stimulating nerves in your ear could improve the health of your heart, researchers have discovered.

A team at the University of Leeds used a standard TENS machine like those designed to relieve labour pains to apply electrical pulses to the tragus, the small raised flap at the front of the ear immediately in front of the ear canal.

The stimulation changed the influence of the nervous system on the heart by reducing the nervous signals that can drive failing hearts too hard.

Professor Jim Deuchars, Professor of Systems Neuroscience in the University of Leeds’ Faculty of Biological Sciences, said: “You feel a bit of a tickling sensation in your ear when the TENS machine is on, but it is painless. It is early days—so far we have been testing this on healthy subjects—but we think it does have potential to improve the health of the heart and might even become part of the treatment for heart failure.”

The researchers applied electrodes to the ears of 34 healthy people and switched on the TENS (Transcutaneous electrical nerve stimulation) machines for 15-minute sessions. They monitored the variability of subjects’ heartbeats and the activity of the part of the nervous system that drives the heart. Monitoring continued for 15 minutes after the TENS machine was switched off.

Lead researcher Dr Jennifer Clancy, of the University of Leeds’ School of Biomedical Sciences, said: “The first positive effect we observed was increased variability in subjects’ heartbeats. A healthy heart does not beat like a metronome. It is continually interacting with its environment—getting a little bit faster or a bit slower depending on the demands on it. An unhealthy heart is more like a machine constantly banging out the same beat. We found that when you stimulate this nerve you get about a 20% increase in heart rate variability.”

The second positive effect was in suppressing the sympathetic nervous system, which drives heart activity using adrenaline.

Dr Clancy said: “We measured the nerve activity directly and found that it reduced by about 50% when we stimulated the ear. This is important because if you have heart disease or heart failure, you tend to have increased sympathetic activity. This drives your heart to work hard, constricts your arteries and causes damage. A lot of treatments for heart failure try to stop that sympathetic activity—beta-blockers, for instance, block the action of the hormones that implement these signals. Using the TENS, we saw a reduction of the nervous activity itself.”

The researchers found significant residual effects, with neither heart rate variability or sympathetic nerve activity returning to the baseline 15 minutes after the TENS machine had been switched off.

The technique works by stimulating a major nerve called the vagus, which has an important role in regulating vital organs such as the heart. There is a sensory branch of the vagus in the outer ear and, by sending electrical current down the nerves and into the brain, researchers were able to influence outflows from the brain that regulate the heart. Vagal nerve stimulation has previously been used to treat conditions including epilepsy.

Professor Deuchars said: “We now need to understand how big and how lasting the residual effect on the heart is and whether this can help patients with heart problems, probably alongside their usual treatments. The next stage will be to conduct a pre-clinical study in heart failure patients.”

Many people listen to loud music without realizing that this can affect their hearing. This could lead to difficulties in understanding speech during age-related hearing loss which affects up to half of people over the age of 65.

New research led by the University of Leicester has examined the cellular mechanisms that underlie hearing loss and tinnitus triggered by exposure to loud sound.

It has demonstrated that physical changes in myelin itself -the coating of the auditory nerve carrying sound signals to the brain – affect our ability to hear.

Dr Martine Hamann, Lecturer in Neurosciences at the University of Leicester, said: “People who suffer from hearing loss have difficulties in understanding speech, particularly when the environment is noisy and when other people are talking nearby.

“Understanding speech relies on fast transmission of auditory signals. Therefore it is important to understand how the speed of signal transmission gets decreased during hearing loss. Understanding these underlying phenomena means that it could be possible to find  medicines to improve auditory perception, specifically in noisy backgrounds.”

The research, funded by Action on Hearing Loss, and led by Leicester, was done in collaboration with Dr Angus Brown of the University of Nottingham. The research, Computational modelling of the effects of auditory nerve dysmyelination is published in Frontiers in Neuroanatomy.

Dr Ralph Holme, Head of Biomedical Research at Action on Hearing Loss, the only UK charity dedicated to funding research into hearing loss said: “There is an urgent need for effective treatments to prevent hearing loss - a condition that affects 10 million people in the UK and all too often isolates people from friends and family. This research further increases our understanding of the biological consequences of exposure to loud noise. Knowledge that we hope will lead to effective treatments for hearing loss within a generation.”

In previous research, researchers have shown that after exposure to loud sounds leading to hearing loss, the myelin coat surrounding the auditory nerve becomes thinner. An important property of auditory signal transmission consists of electrical signals “jumping” from one myelin domain to the other. Those domains, called Nodes of Ranvier, become elongated after exposure to loud sound.

Dr Hamann said: “Although we showed that transmission of auditory signals (electrical signals transmitted along the auditory nerve) was slowed down after exposure to loud sound leading to hearing loss, the question remained: Is this due to the actual change of the physical properties of the myelin or is it due to the redistribution of channels occurring subsequent to those changes?

“This work is a theoretical work whereby we tested the hypothesis that myelin was the prime reason for the decreased signal transmission. We simulated how physical changes to the myelin and/or redistribution of channels influenced the signal transmission along the auditory nerve. We found that the redistribution of channels had only small effect on the conduction velocity whereas physical changes to myelin were primarily responsible for the effects.”

The research has shown for the first time the closer links between a deficit in the “myelin” sheath surrounding the auditory nerve and hearing loss. “This research is innovative because data modelling (simulations) was used on previous morphological data and assessed that physical changes to the myelin coat were the principal cause of the deficit,” said Dr Hamman.

“We have come closer to understanding the reasons behind deficits in auditory perception. This means that we can also get closer to target those deficits, for example by promoting myelin repair after acoustic trauma or during age related hearing loss.”

Dr Hamann said the work will help prevention as well as progression into finding appropriate cures for hearing loss and possibly tinnitus developing from hearing loss.

“The sense of achievement comes from the fact that it could help ageing people to better understand their relatives on the phone,” said Dr Hamann.

The next step is to test drugs that could promote myelin repair and improve hearing after hearing loss.

Researchers at the Beckman Institute at the University of Illinois at Urbana-Champaign have developed a new technique that can noninvasively image the pulse pressure and elasticity of the arteries of the brain, revealing correlations between arterial health and aging.

Brain artery support, which makes up the cerebrovascular system, is crucial for healthy brain aging and preventing diseases like Alzheimer’s and other forms of dementia.

The researchers, led by Monica Fabiani and Gabriele Gratton, psychology professors in the Cognitive Neuroscience Group, routinely record optical imaging data by shining near-infrared light into the brain to measure neural activity. Their idea to measure pulse pressure through optical imaging came from observing in previous studies that the arterial pulse produced strong signals in the optical data, which they normally do not use to study brain function. Realizing the value in this overlooked data, they launched a new study that focused on data from 53 participants aged 55-87 years. 

“When we image the brain using our optical methods, we usually remove the pulse as an artifact—we take it out in order to get to other signals from the brain,” said Fabiani. “But we are interested in aging and how the brain changes with other bodily systems, like the cardiovascular system. When thinking about this, we realized it would be useful to measure the cerebrovascular system as we worry about cognition and brain physiology.”

The initial results using this new technique find that arterial stiffness is directly correlated with cardiorespiratory fitness: the more fit people are, the more elastic their arteries. Because arterial stiffening is a cause of reduced brain blood flow, stiff arteries can lead to a faster rate of cognitive decline and an increased chance of stroke, especially in older adults.

Using this method, the researchers were able to collect additional, region-specific data.

“In particular, noninvasive optical methods can provide estimates of arterial elasticity and brain pulse pressure in different regions of the brain, which can give us clues about the how different regions of the brain contribute to our overall health,” said Gratton. “For example, if we found that a particular artery was stiff and causing decreased blood flow to and loss of brain cells in a specific area, we might find that the damage to this area is also associated with an increased likelihood of certain psychological and cognitive issues.”

The researchers are investigating ways to use this technique to measure arterial stiffness across different age groups and specific cardiovascular or stress levels. High levels of stress, especially over a long amount of time, may affect arterial health, according to the researchers. 

“This is just the beginning of what we’re able to explore with this technique. We’re looking at other age groups, and in the future we intend to study people with varying levels of long-term stress,” said Fabiani. “When people are stressed for long periods of time, like if they’re caring for a sick parent, stress might generate vasoconstriction and higher blood pressure, with significant consequences for arterial function in the brain. We are interested in knowing whether this may be an important factor leading to arterial stiffness.” 

The researchers are also able to gather information about pulse transit time, or how long it takes the blood to flow through the brain’s arteries, and visualize large arteries running along the brain surface.

“Our goal is to find more information about what causes arterial stiffness, and how regional arterial stiffness can lead to specific health problems. Our findings continue to bolster the idea that an important key to aging well is having good cerebrovascular health,” said Fabiani.

When investigators at the Stanford University School of Medicine applied light-driven stimulation to nerve cells in the brains of mice that had suffered strokes several days earlier, the mice showed significantly greater recovery in motor ability than mice that had experienced strokes but whose brains weren’t stimulated.

These findings, published online Aug. 18 in Proceedings of the National Academy of Sciences, could help identify important brain circuits involved in stroke recovery and usher in new clinical therapies for stroke, including the placement of electrical brain-stimulating devices similar to those used for treating Parkinson’s disease, chronic pain and epilepsy. The findings also highlight the neuroscientific strides made possible by a powerful research technique known as optogenetics.

Stroke, with 15 million new victims per year worldwide, is the planet’s second-largest cause of death, according to Gary Steinberg, MD, PhD, professor and chair of neurosurgery and the study’s senior author. In the United States, stroke is the largest single cause of neurologic disability, accounting for about 800,000 new cases each year — more than one per minute — and exacting an annual tab of about $75 billion in medical costs and lost productivity.

The only approved drug for stroke in the United States is an injectable medication called tissue plasminogen activator, or tPA. If infused within a few hours of the stroke, tPA can limit the extent of stroke damage. But no more than 5 percent of patients actually benefit from it, largely because by the time they arrive at a medical center the damage is already done. No pharmacological therapy has been shown to enhance recovery from stroke from that point on.

Enhancing recovery

But in this study — the first to use a light-driven stimulation technology called optogenetics to enhance stroke recovery in mice — the stimulations promoted recovery even when initiated five days after stroke occurred.

“In this study, we found that direct stimulation of a particular set of nerve cells in the brain — nerve cells in the motor cortex — was able to substantially enhance recovery,” said Steinberg, the Bernard and Ronni Lacroute-William Randolph Hearst Professor in Neurosurgery and Neurosciences.

About seven of every eight strokes are ischemic: They occur when a blood clot cuts off oxygen flow to one or another part of the brain, destroying tissue and leaving weakness, paralysis and sensory, cognitive and speech deficits in its wake. While some degree of recovery is possible — this varies greatly among patients depending on many factors, notably age — it’s seldom complete, and typically grinds to a halt by three months after the stroke has occurred.

Animal studies have indicated that electrical stimulation of the brain can improve recovery from stroke. However, “existing brain-stimulation techniques activate all cell types in the stimulation area, which not only makes it difficult to study but can cause unwanted side effects,” said the study’s lead author, Michelle Cheng, PhD, a research associate in Steinberg’s lab.

For the new study, the Stanford investigators deployed optogenetics, a technology pioneered by co-author Karl Deisseroth, MD, PhD, professor of psychiatry and behavioral sciences and of bioengineering. Optogenetics involves expressing a light-sensitive protein in specifically targeted brain cells. Upon exposure to light of the right wavelength, this light-sensitive protein is activated and causes the cell to fire.

Steinberg’s team selectively expressed this protein in the brain’s primary motor cortex, which is involved in regulating motor functions. Nerve cells within this cortical layer send outputs to many other brain regions, including its counterpart in the brain’s opposite hemisphere. Using an optical fiber implanted in that region, the researchers were able to stimulate the primary motor cortex near where the stroke had occurred, and then monitor biochemical changes and blood flow there as well as in other brain areas with which this region was in communication. “We wanted to find out whether activating these nerve cells alone can contribute to recovery,” Steinberg said.

Walking farther

By several behavioral, blood flow and biochemical measures, the answer two weeks later was a strong yes. On one test of motor coordination, balance and muscular strength, the mice had to walk the length of a horizontal beam rotating on its axis, like a rotisserie spit. Stroke-impaired mice whose primary motor cortex was optogenetically stimulated did significantly better in how far they could walk along the beam without falling off and in the speed of their transit, compared with their unstimulated counterparts.

The same treatment, applied to mice that had not suffered a stroke but whose brains had been similarly genetically altered and then stimulated just as stroke-affected mice’s brains were, had no effect on either the distance they travelled along the rotating beam before falling off or how fast they walked. This suggests it was stimulation-induced repair of stroke damage, not the stimulation itself, yielding the improved motor ability.

Stroke-affected mice whose brains were optogenetically stimulated also regained substantially more of their lost weight than unstimulated, stroke-affected mice. Furthermore, stimulated post-stroke mice showed enhanced blood flow in their brain compared with unstimulated post-stroke mice.

In addition, substances called growth factors, produced naturally in the brain, were more abundant in key regions on both sides of the brain in optogenetically stimulated, stroke-affected mice than in their unstimulated counterparts. Likewise, certain brain regions of these optogenetically stimulated, post-stroke mice showed increased levels of proteins associated with heightened ability of nerve cells to alter their structural features in response to experience — for example, practice and learning. (Optogenetic stimulation of the brains of non-stroke mice produced no such effects.)

Steinberg said his lab is following up to determine whether the improvement is sustained in the long term. “We’re also looking to see if optogenetically stimulating other brain regions after a stroke might be equally or more effective,” he said. “The goal is to identify the precise circuits that would be most amenable to interventions in the human brain, post-stroke, so that we can take this approach into clinical trials.”

Everyone knows that neurons are the key to how the brain operates. But it turns out they aren’t the only stars in the show; neighboring cells called astrocytes are quickly gaining increasing respect for the critical role they play in memory and learning. EPFL scientists have recently outlined the molecular mechanics of this process in an article published in Proceedings of the National Academy of Sciences (PNAS). Lactate produced by the star-shaped astrocytes accelerates the memorization process. This result, surprising until very recently, opens up new possibilities for treating cognitive and memory disorders, as well as psychiatric conditions such as depression.

Our brains are greedy, gobbling up as much as 25% of our daily energy consumption. Neurons and astrocytes thrive on glucose. Neurons use it to protect themselves from the buildup of toxic products resulting from their activity. Astrocytes, which are glial cells (as opposed to neurons), manufacture lactate; this was long thought to be a byproduct of glucose metabolism, and then as a simple energy source for neurons.

In 2011, research published in the journal Cell by EPFL’s Laboratory of Neuroenergetics and Cellular Dynamics in collaboration with a U.S. team unveiled the critical role of lactate. “In vivo, when the transfer of lactate from astrocytes to neurons is blocked, we found that the memorization process was also blocked,” explains EPFL professor Pierre Magistretti, head of the lab. “We thus knew that it was an essential fuel for that process.”

Focusing their attention on the molecular mechanism, the scientists discovered that lactate provides more than just energy. It acts as a moderator of one type of glutamate receptor (NMDA receptors), the nervous system’s primary neurotransmitter. This glutamate receptor is involved in the memorization process, and the research demonstrates that lactate gives them what amounts to a turbo-boost. “Glutamate lets you drive in first gear; with lactate, you can shift into fourth and travel at 100 km/h,” says Magistretti.

Palliating cognitive deficits
The scientists did their initial research in vitro. They exposed mice neurons to various substances and measured their effect on the expression of genes involved in memory. Glucose and pyruvate (another glucose derivative) didn’t have any effect. A lactate supplement, on the other hand, triggered the expression of four genes involved in cerebral plasticity that are essential to memorization.

They followed this work with in vivo studies, which confirmed their results. They administered lactate into the brains of living mice, and then extracted the tissues and measured gene expression. Once again, the expression of genes involved in cerebral plasticity increased significantly.

Could we take lactate supplements and develop encyclopedic memory? Magistretti’s lab has just received a grant to study the effects of artificial lactate supplementation. “We have identified a series of molecules that can make astrocytes produce more lactate. Now the idea is to see in vivo if we can mitigate cognitive deficits and memory disorders.” In addition, since conditions such as depression are often accompanied by cognitive problems, “lactate could also have an antidepressant effect,” says Magistretti, who also conducts research at the National Center for Competence in Research Synapsy, dedicated to the understanding of the synaptic basis of psychiatric disease.

Our individual genetic make-up determines the effect that stress has on our emotional centres. These are the findings of a group of researchers from the MedUni Vienna. Not every individual reacts in the same way to life events that produce the same degree of stress. Some grow as a result of the crisis, whereas others break down and fall ill, for example with depression. The outcome is determined by a complex interaction between depression gene versions and environmental factors.

The Vienna research group, together with international cooperation partners, have demonstrated that there are interactions between stressful life events and certain risk gene variants that subsequently change the volume of the hippocampus forever.

The hippocampus is a switching station in the processing of emotions and acts like a central interface when dealing with stress. It is known to react very sensitively to stress. In situations of stress that are interpreted as a physical danger (‘distress’), it shrinks in size, which is a phenomenon observed commonly in patients with depression and one which is responsible for some of their clinical symptoms. By contrast, positive stress (‘eustress’), of the kind that can occur in emotionally exciting social situations can actually cause the hippocampus to increase in size.

According to the results of the study, just how stressful life events impact on the size of the hippocampus depends on more than just environmental factors. There are genes that determine whether the same life event causes an increase or decrease in the volume of the hippocampus, and which therefore defines whether the stress is good or bad for our brain. The more risk genes an individual has, the more negative an impact the “life events” have on the size of the hippocampus. Where there are no or only a few risk genes, this life event can actually have a positive effect.

Examining life crises
As part of the study, carried out at the University Department of Psychiatry and Psychotherapy (led by Siegfried Kasper), the study team obtained quantitative information from healthy test subjects about stressful life events, such as deaths in the family, divorce, unemployment, financial losses, relocations, serious illnesses or accidents.

A high-resolution anatomical magnetic resonance scan was also carried out (at the High-Field MR Centre of Excellence, Department of MR Physics, led by Ewald Moser). The University Department of Laboratory Medicine (Harald Esterbauer and colleagues) carried out the gene analyses (COMT Val158Met, BDNF Val66Met, 5-HTTLPR). At the University Department of Psychiatry and Psychotherapy, primary author Ulrich Rabl measured the volume of the test subjects’ hippocampi using computer-assisted techniques and analysed the results in the context of the genetic and environmental data.
"People with the three gene versions believed to encourage depression had a smaller hippocampus than those with fewer or none of these gene versions, even though they had the same number of stressful life events," says study leader Lukas Pezawas, describing the results. People with only one or even none of the risk genes, on the other hand, had an enlarged hippocampus with similar life events.

The study highlights the importance of gene and environment interaction as a determining factor for the volume of the hippocampus. “These results are important for understanding neurobiological processes in stress-associated illnesses such as depression or post-traumatic stress disorder. It is ultimately our genes that determine whether stress makes us psychologically unwell or whether it encourages our mental health,” explains Pezawas.

The study, published in the highly respected “Journal of Neuroscience”, was funded by a special research project of the FWF (Austrian Science Fund) (SFB-35, led by Harald Sitte) and presented as a highlight at the international conference on “Organization for Human Brain Mapping”.

A team led by researchers at the University of Exeter Medical School and King’s College London has uncovered some of the strongest evidence yet that epigenetic changes in the brain play a role in Alzheimer’s disease.

Epigenetic changes affect the expression or activity of genes without changing the underlying DNA sequence and are believed to be one mechanism by which the environment can interact with the genome. Importantly, epigenetic changes are potentially reversible and may therefore provide targets for the development of new therapies.

Globally, more than 26 million people are currently affected by Alzheimer’s Disease. As this number grows in line with an increasingly aging population, the need to identify new disease mechanisms is more important than ever. Post-mortem examinations have revealed much about how Alzheimer’s damages the brain, with some regions, such as the entorhinal cortex, being particularly susceptible, while others, such as the cerebellum, remain virtually unscathed. However, little is yet known about how and why the disease develops in specific brain regions.

The current study found that chemical modifications to DNA within the ANK1 gene are strongly associated with measures of neuropathology in the brain. The study, published in Nature Neuroscience, found that people with more Alzheimer’s disease-related neuropathology in their brains had higher levels of DNA modifications within the ANK1 gene. The finding was particularly strong in the entorhinal cortex, and also detected in other cortical regions affected by the disease. In contrast, no significant changes were observed in less affected brain regions or blood.

Professor Jonathan Mill, of the University of Exeter Medical School and King’s College London, who headed the study, said: “This is the strongest evidence yet to suggest that epigenetic changes in the brain occur in Alzheimer’s disease, and offers potential hope for understanding the mechanisms involved in the onset of dementia. We don’t yet know why these changes occur – it’s possible that they are involved in disease onset, but they may also reflect changes induced by the disease itself.”

Dr Katie Lunnon, first author on the study, from the University of Exeter Medical School, added: “It’s intriguing that we find changes specifically in the regions of the brain involved in Alzheimer’s disease. Future studies will focus on isolating different cell-types from the brain to see whether these changes are neuron-specific.”

In addition to the University of Exeter Medical School and King’s College London, the team included contributors from The Icahn School of Medicine at Mount Sinai, the JJ Peters VA Medical Center, The Johns Hopkins University School of Medicine, Harvard Medical School, the University of Oxford, and Rush University Medical Center, Chicago. They used cutting-edge technology to examine brain tissue from different areas of the brain across three cohorts - the MRC London Brain Bank for Neurodegenerative Disease, the Oxford Thomas Willis Brain Bank, and the Mount Sinai Alzheimer’s Disease and Schizophrenia Brain Bank. They analysed three cortical regions, cerebellum, and blood obtained from several hundred individuals representing the spectrum of disease; from those with no evidence of dementia and neurodegeneration, through to patients with very advanced disease.

The research was primarily funded by the National Institutes of Health (NIH), U.S. Department of Health and Human Services, as part of its Epigenomics Roadmap Initiative (grant number R01-AG036039 awarded to Jonathan Mill). To learn more about the NIH initiative that seeks to accelerate research into the relatively new and fast-developing area of epigenetics, go to: https://commonfund.nih.gov/epigenomics/index.

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, who also provided funding for the study said:“We know that changes to the DNA code of certain genes are associated with an increased risk of developing Alzheimer’s disease. Investigating how epigenetic changes influence genes in Alzheimer’s is still a relatively new area of study. The importance of understanding this area of research is highlighted by the fact that epigenetic changes have been associated with development of other diseases, including cancer.

“This innovative research has discovered a potential new mechanism involved in Alzheimer’s by linking the ANK1 gene to the disease. We will be interested to see further research into the role of ANK1 in Alzheimer’s and whether other epigenetic changes may be involved in the disease.

“Alzheimer’s affects millions of people worldwide and we need pioneering research to understand exactly why the disease occurs. Alzheimer’s Research UK is helping to fund research which will take us a step closer to understanding and defeating this devastating disease.”

A new study led by researchers at Brigham and Women’s Hospital (BWH) and Rush University Medical Center, reveals how early changes in brain DNA methylation are involved in Alzheimer’s disease. DNA methylation is a biochemical alteration of the building blocks of DNA and is one of the markers that indicate whether the DNA is open and biologically active in a given region of the human genome.

The study is published online August 17, 2014 in Nature Neuroscience.

According to the researchers, this is the first large-scale study employing epigenome-wide association (EWAS) studies—which look at chromosomal make-up and changes—in relation to the brain and Alzheimer’s disease.

"Our study approach may help us to better understand the biological impact of environmental risk factors and life experiences on Alzheimer’s disease," said Philip L. De Jager, MD, PhD, Program in Translational Neuropsychiatric Genomics, BWH Departments of Neurology and Psychiatry, lead study author. "There are certain advantages to studying the epigenome, or the chemical changes that occur in DNA. The epigenome is malleable and may harbor traces of life events that influence disease susceptibility, such as smoking, depression and menopause, which may influence susceptibility to Alzheimer’s and other diseases."

The researchers analyzed samples from 708 donated brains from subjects in the Religious Orders Study and Rush Memory and Aging Project, conducted by study co-author, David A. Bennett, MD, Rush Alzheimer’s Disease Center in Chicago. They found that methylation levels correlated with Alzheimer’s disease in 71 of 415,848 CpG markers analyzed (these are a pair of DNA building blocks consisting of a cytosine and a guanine nucleotide that are located next to each other). These 71 markers were found in the ANK1 and RHBDF2 genes, as well as ABCA7 and BIN1 which harbor known Alzheimer’s disease susceptibility variants.

Further, investigation of these CpG associations revealed nearby genes whose RNA expression was altered in brain samples with Alzheimer’s disease: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. This suggests that the CpG associations identify genes whose function is altered in Alzheimer’s disease.

Further, “because these findings are also found in the subset of subjects that are not cognitively impaired at the time of death, it appears that these DNA methylation changes may play a role in the onset of Alzheimer’s disease,” said De Jager. “Moreover, our work has helped identify regions of the human genome that are altered over the life-course in a way that is associated with Alzheimer’s disease. This may provide clues to treating the disease by using drugs that influence epigenomic function.”

According to the CDC, unintentional injuries are the leading cause of death for adolescents. Compared to the two leading causes of death for all Americans, heart disease and cancer, a pattern of questionable decision-making in dire situations comes to light in teen mortality. New research from the Center for BrainHealth at The University of Texas at Dallas investigating brain differences associated with risk-taking teens found that connections between certain brain regions are amplified in teens more prone to risk.

“Our brains have an emotional-regulation network that exists to govern emotions and influence decision-making,” explained the study’s lead author, Sam Dewitt. “Antisocial or risk-seeking behavior may be associated with an imbalance in this network.”

The study, published June 30 in Psychiatry Research: Neuroimaging, looked at 36 adolescents ages 12-17; eighteen risk-taking teens were age- and sex-matched to a group of 18 non-risk-taking teens. Participants were screened for risk-taking behaviors, such as drug and alcohol use, sexual promiscuity, and physical violence and underwent functional MRI (fMRI) scans to examine communication between brain regions associated with the emotional-regulation network. Interestingly, the risk-taking group showed significantly lower income compared to the non-risk taking group.

“Most fMRI scans used to be done in conjunction with a particular visual task. In the past several years, however, it has been shown that performing an fMRI scan of the brain during a ‘mind-wandering’ state is just as valuable,”said Sina Aslan, Ph.D., President of Advance MRI and Adjunct Assistant Professor at the Center for BrainHealth at The University of Texas at Dallas.“In this case, brain regions associated with emotion and reward centers show increased connection even when they are not explicitly engaged.”

The study, conducted by Francesca Filbey, Ph.D., Director of Cognitive Neuroscience Research of Addictive Behaviors at the Center for BrainHealth and her colleagues, shows that risk-taking teens exhibit hyperconnectivity between the amygdala, a center responsible for emotional reactivity, and specific areas of the prefrontal cortex associated with emotion regulation and critical thinking skills. The researchers also found increased activity between areas of the prefrontal cortex and the nucleus accumbens, a center for reward sensitivity that is often implicated in addiction research.

“Our findings are crucial in that they help identify potential brain biomarkers that, when taken into context with behavioral differences, may help identify which adolescents are at risk for dangerous and pathological behaviors in the future,” Dewitt explained.

He also points out that even though the risk-taking group did partake in risky behavior, none met clinical criteria for behavioral or substance use disorders.

By identifying these factors early on, the research team hopes to have a better chance of providing effective cognitive strategies to help risk-seeking adolescents regulate their emotions and avoid risk-taking behavior and substance abuse.

Kessler stroke researchers and colleagues have identified an association between over-optimistic estimation of one’s own ability to take medications accurately, and memory loss among stroke survivors. Results indicate that assessing patients for their ability to estimate medication skills accurately may predict memory disorder. The article, “Stroke survivors over-estimate their medication self-administration ability (MSA), predicting memory loss,” was epublished ahead of print on May 28 by Brain Injury. The authors are AM Barrett, MD, and J Masmela of Kessler Foundation, Elizabeth E Galletta of Hunter College, Jun Zhang of St. Charles Hospital, Port Jefferson, NY, and Uri Adler, MD, of Kessler Institute for Rehabilitation.

Researchers compared 24 stroke survivors with 17 controls, using the Hopkins Medication Schedule to assess MSA, the Geriatric Depression Scale to assess mood, and the Hopkins Verbal Test and Mini-Mental State Examination to assess memory. Results showed that stroke survivors over-estimated their MSA in comparison to controls. Over-estimation of MSA correlated strongly with verbal memory deficit.

Strategies that enhance adherence to medication are a public health priority. “Few studies, however, have looked at cognitive factors that may interfere with MSA,” commented Dr. Barrett. “While some stroke survivors have obvious cognitive deficits, many people are not aware that stroke survivors can be intelligent and high functioning, but still have trouble with thinking that can cause errors in medication self-management. These individuals may not realize their own deficits, a condition called cognitive anosognosia. Screening stroke survivors for MSA may be a useful approach to identifying memory deficits that hinder rehabilitation and community participation and contribute to poor outcomes.”

Larger studies of left and right stroke survivors need to be conducted in the community and rehabilitation settings in order to determine the underlying mechanisms for both over-estimation and under-estimation of self-performance.

New Penn Medicine research shows that neuropsychiatric symptoms such as depression, anxiety and fatigue are more common in newly diagnosed Parkinson’s disease (PD) patients compared to the general population. The study also found that initiation of dopamine replacement therapy, the most common treatment for PD, was associated with increasing frequency of impulse control disorders and excessive daytime sleepiness. The new findings, the first longitudinal study to come out of the Parkinson’s Progression Markers Initiative (PPMI), are published in the August 15, 2014, issue of Neurology®, the medical journal of the American Academy of Neurology.

The PPMI, a landmark, multicenter observational clinical study sponsored by The Michael J. Fox Foundation for Parkinson’s Research, uses a combination of advanced imaging, biologics sampling and behavioral assessments to identify biomarkers of Parkinson’s disease progression. The Penn study, which represents neuropsychiatric and cognitive data from baseline through the first 24 months of follow up, was conducted in collaboration with the Philadelphia VA Medical Center and the University Hospital Donostia in Spain.

The study examined 423 newly diagnosed, untreated Parkinson’s patients and 196 healthy controls at baseline and 281 people with PD at six months. Of these, 261 PD patients and 145 healthy controls were evaluated at 12 months, and 96 PD patients and 83 healthy controls evaluated at 24 months.

PD patients were permitted to begin dopamine therapy at any point after their baseline evaluation.

“We hypothesized that neuropsychiatric symptoms would be common and stable in severity soon after diagnosis and that the initiation of dopamine replacement therapy would modify their natural progression in some way,” says senior author, Daniel Weintraub, MD, associate professor of Psychiatry and Neurology at the Perelman School of Medicine at the University of Pennsylvania and a fellow in Penn’s Institute on Aging.

The Penn team showed that while there was no significant difference between PD patients and healthy controls in the frequency of impulse control disorders, a neuropsychiatric symptom that can lead to compulsive gambling, sexual behavior, eating or spending, 21 percent of newly diagnosed PD patients screened positive for such symptoms at baseline. That percentage did not increase significantly over the 24-month period.

However, six patients who had been on dopamine therapy for more than a year at the 24-month evaluation showed impulse control disorders or related behavior symptoms while no impulse control incident symptoms were reported in PD patients who had not commenced dopamine therapy. Dopamine therapy did help with fatigue, with 33 percent of patients improving their fatigue test score over 24 months compared with only 11 percent of patients not on dopamine therapy.

The investigators also found evidence that depression may be undertreated in early PD patients: Two-thirds of patients who screened positive for depression at any time point were not taking an antidepressant.

PPMI follows volunteers for five years, so investigators plan to expand upon these results, which Weintraub still considers preliminary. “We will more closely look at cognitive changes over time,” he says. “Two years is not a sufficient period of follow up to really look at meaningful cognitive decline.”

The perspective of time is what makes the PPMI such an important initiative, Weintraub points out, since many patients with the disease live for 10 to 20 years following their diagnosis. “It’s really a chance to assess the frequency and characteristics of psychiatric and cognitive symptoms in PD, compare it with healthy controls, and then also look at its evolution over time,” he says. “The hope is that we will be able to continue this work so that we can obtain long-term follow up data on these patients,” says Weintraub.

Depression is known to be a common symptom of Parkinson’s disease, but remains untreated for many patients, according to a new study by Northwestern Medicine investigators in collaboration with the National Parkinson’s Foundation (NPF).

In fact, depression is the most prevalent non-motor symptom of Parkinson’s, a chronic neurodegenerative disorder typically associated with movement dysfunction.  

“We confirmed suspicion that depression is a very common symptom in Parkinson’s disease. Nearly a quarter of the people in the study reported symptoms consistent with depression,” said Danny Bega, MD, ’14 GME, instructor in the Ken and Ruth Davee Department of Neurology and first author of the study. “This is important because previous research has determined that depression is a major determinant of overall quality of life.”

Using the NPS’s patient database, the investigators looked at records of more than 7,000 people with Parkinson’s disease. Among those with high levels of depressive symptoms, only one-third had been prescribed antidepressants before the study began, and even fewer saw social workers or mental health professionals for counseling.

The investigators then focused their analysis on the remaining two-thirds of patients with depressive symptoms who were not receiving treatment at the start of the study. Throughout a year of observation, less than 10 percent of them received prescriptions for antidepressants or referrals to counseling. Physicians were most likely to identify depression and advocate treatment for patients with the severest depression scores.

The findings were published in the Journal of Parkinson’s Disease.

“The majority of these patients remained untreated,” said Dr. Bega. “Still, the physician recognition of depression in this population was actually better than previous reports had suggested.”

However, recognition may be lower for the general population of patients with Parkinson’s disease – the patients in this study visited medical centers deemed “Centers of Excellence” by the NPF.

“Physicians must be more vigilant about screening patients for depression as part of a routine assessment of Parkinson’s disease, and the effectiveness of different treatments for depression in this population need to be assessed,” said Dr. Bega.

Following another person’s gaze can reveal a wealth of information critical to social interactions and also to safety. Gaze following typically emerges in infancy, and new research looking at preterm infants suggests that it’s visual experience, not maturational age, that underlies this critical ability.

The research is published in Psychological Science, a journal of the Association for Psychological Science.

“To the best of our knowledge, this is the first study showing that some aspects of the early development of social cognition is influenced by experience, even when the human brain is highly immature,” says psychological scientist Marcela Peña of Pontificia Universidad Católica de Chile, lead researcher on the study. “Our results are important for modeling early cognitive development.”

Previous research on early cognitive development suggests that some cognitive functions develop only after the brain has matured sufficiently, while other cognitive functions develop in response to a rich social environment.

To disentangle the roles played by neural maturation and environmental exposure in relation to gaze following, Peña and colleagues decided to compare the gaze following abilities of preterm and full-term infants.

“Because preterm infants are exposed to face-to-face interactions earlier (in terms of postmenstrual age) than infants who are born at term, they may become sensitive to gaze direction sooner as well,” the researchers explain.

A total of 81 healthy infants participated in the study and they were split into four groups: Full-term 4-month-olds, full-term 7-month-olds, preterm 7-month-olds, and preterm 10-month-olds.

The preterm infants were born 2.5 to 3 months early – thus, full-term 4-month-olds and preterm 7-month-olds had an equivalent postmenstrual age of about 13 months, but the preterm 7-month-olds had an additional 2.5 to 3 months of visual experience as a result of having entered the world early.

While sitting in his or her mother’s lap, the infants were presented with a sound and visual cue to grab their attention. As soon as they were looking at the screen, a video of a woman appeared and the woman made peek-a-boo like gestures. The woman then turned her head and directed her gaze toward one side of the screen; subsequently, a moving toy appeared on each side of the screen. Using an eyetracking system adapted for infants, the researchers were able to monitor which side of the screen infants looked to first. The researchers repeated this procedure with each infant 20 times.

The data showed that preterm 7-month-olds and preterm 10-month-olds behaved like full-term 7-month-olds, looking to the toy on the side of the screen indicated by the woman’s gaze. Full-term 4-month-olds, on the other hand, tended to look randomly to either side.

This pattern of results held even when the woman indicated direction with only her eyes, while her head continued to face forward.

Together, these findings suggest that exposure to visual experience outside the womb may matter most for early gaze following.

“Combined with previous results on vision and language cognition, our results support the idea that the early steps of human cognition develops in an asynchronous way,” says Peña. “Some systems are more or less sensitive to external stimulation, but others can be more influenced by biological maturation.”

A new technique developed by Elisa Konofagou, professor of biomedical engineering and radiology at Columbia Engineering, has demonstrated for the first time that the size of molecules penetrating the blood-brain barrier (BBB) can be controlled using acoustic pressure—the pressure of an ultrasound beam—to let specific molecules through. The study was published in the July issue of the Journal of Cerebral Blood Flow & Metabolism.

“This is an important breakthrough in getting drugs delivered to specific parts of the brain precisely, non-invasively, and safely, and may help in the treatment of central nervous system diseases like Parkinson’s and Alzheimer’s,” says Konofagou, whose National Institutes of Health Research Project Grant (R01) funding was just renewed for another four years for an additional $2.22 million. The award is for research to determine the role of the microbubble in controlling both the efficacy and safety of drug safety through the BBB with a specific application for treating Parkinson’s disease.

Most small—and all large—molecule drugs do not currently penetrate the blood-brain barrier that sits between the vascular bed and the brain tissue. “As a result,” Konofagou explains, “all central nervous system diseases remain undertreated at best. For example, we know that Parkinson’s disease would benefit by delivery of therapeutic molecules to the neurons so as to impede their slow death. But because of the virtually impermeable barrier, these drugs can only reach the brain through direct injection and that requires anesthesia and drilling the skull while also increasing the risk of infection and limiting the number of sites of injection. And transcranial injections rarely work—only about one in ten is successful.”

Focused ultrasound in conjunction with microbubbles—gas-filled bubbles coated by protein or lipid shells—continues to be the only technique that can permeate the BBB safely and non-invasively. When microbubbles are hit by an ultrasound beam, they start oscillating and, depending on the magnitude of the pressure, continue oscillating or collapse. While researchers have found that focused ultrasound in combination with microbubble cavitation can be successfully used in the delivery of therapeutic drugs across the BBB, almost all earlier studies have been limited to one specific-sized agent that is commercially available and widely used clinically as ultrasound contrast agents. Konofagou and her team were convinced there was a way to induce a size-controllable BBB opening, enabling a more effective method to improve localized brain drug delivery.

Konofagou targeted the hippocampus, the memory center of the brain, and administered different-sized sugar molecules (Dextran). She found that higher acoustic pressures led to larger molecules accumulating into the hippocampus as confirmed by fluorescence imaging. This demonstrated that the pressure of the ultrasound beam can be adjusted depending on the size of the drug that needs to be delivered to the brain: all molecules of variant sizes were able to penetrate the opened barrier but at distinct pressures, i.e., small molecules at lower pressures and larger molecules at higher pressures.

“Through this study, we’ve been able to show, for the first time, that we can control the BBB opening size through the use of acoustic pressure,” says Konofagou. “We’ve also learned much more about the physical mechanisms associated with the trans-BBB delivery of different-sized agents, and understanding the BBB mechanisms will help us to develop agent size-specific focused ultrasound treatment protocols.”

Konofagou and her Ultrasound Elasticity Imaging Laboratory team plan to continue to work on the treatment of Alzheimer’s and Parkinson’s in a range of models, and hope to test their technique in clinical trials within the next five years.

“It is frightening to think that in the 21st century we still have no idea how to treat most brain diseases,” Konofagou adds. “But we’re really excited because we now have a tool that could potentially change the current dire predictions that come with a neurological disorder diagnosis.”

People with schizophrenia struggle to turn goals into actions because brain structures governing desire and emotion are less active and fail to pass goal-directed messages to cortical regions affecting human decision-making, new research reveals.

Published in Biological Psychiatry, the finding by a University of Sydney research team is the first to illustrate the inability to initiate goal-directed behaviour common in people with schizophrenia.

The finding may explain why people with schizophrenia have difficulty achieving real-world goals such as making friends, completing education and finding employment.

"The apparent lack of motivation in schizophrenic patients isn’t because they lack goals or don’t enjoy rewards and pleasure," says the University of Sydney’s Dr Richard Morris, the study’s lead author.

"They enjoy as many experiences as other people, including food, movies and scenes of natural beauty.

"What appears to block them are specific brain deficits that prevent them from converting their desires and goals into choices and behaviour."

Using a control group research design, the researchers used a two-prong approach to reveal how and why schizophrenics fail to convert their preferences into congruent choices.

First, using a series of experiments involving choosing between different snack food rewards, experimenters revealed that:

• schizophrenic subjects had a liking for snack foods equivalent to healthy adults
• when researchers reduced the value of one of the snacks, both subjects and healthy adults subsequently preferred different snacks, as expected
• surprisingly, schizophrenic subjects had major difficulty choosing their preferred snack when provided with a choice between their preferred snack and the devalued snack.

Second, researchers used functional magnetic resonance imaging (fMRI) to measures brain activity while study subjects performed learning tasks involving snack foods.

This technique relies on the fact that cerebral blood flow and neuronal activity are coupled. When an area of the brain is in use, bloodflow to that region increases, thereby indicating neural activity. This neural activity can be presented graphically by colour-coding the strength of activation across the brain or in specific brain regions. The technique can localise neural activity to within millimetres.

Functional MRI results revealed the following:

• schizophrenic subjects had normal neural activity in the brain region responsible for decision-making (prefrontal cortex)
• among schizophrenic subjects, brain regions responsible, in part, for controlling actions and choice (the caudate) had far lower neural activity than in healthy subjects
• lower neural activity in the caudate regions was correlated with the difficulty that schizophrenic subjects’ had applying their food preferences to obtain future snack foods.

"Pathology in the caudate and associated brain regions may prevent schizophrenic subjects from properly evaluating their desires then transmitting that information to guide their behavior," says Dr Morris.

"This means that desires and goals are intact in people with schizophrenia, however they have difficulty choosing the right course of action to achieve those goals.

"This failure to integrate desire with action means people with schizophrenia are stuck in limbo, wanting a normal life but unable to take the necessary steps to achieve it."

Schizophrenia affects one per cent of people worldwide, including in Australia.

However so-called “poor motivation” in schizophrenia is a major economic concern because it is not treated by current medicines, and often means patients fail to finish their education or hold a full-time job.

People who are aware they are asleep when they are dreaming have better than average problem-solving abilities, new research has discovered.

Experts from the University of Lincoln, UK, say that those who experience ‘lucid dreaming’ – a phenomena where someone who is asleep can recognise that they are dreaming – can solve problems in the waking world better than those who remain unaware of the dream until they wake up.

The concept of lucid dreaming was explored in the 2010 film Inception, where the dreamers were able to spot incongruities within their dream. It is thought some people are able to do this because of a higher level of insight, meaning their brains detect they are in a dream because events would not make sense otherwise. This cognitive ability translates to the waking world when it comes to finding the solution to a problem by spotting hidden connections or inconsistencies, researchers say.

The research was carried out by Dr Patrick Bourke, Senior Lecturer at the Lincoln School of Psychology and his student Hannah Shaw. It is the first empirical study demonstrating the relationship between lucid dreaming and insight.

He said: “It is believed that for dreamers to become lucid while asleep, they must see past the overwhelming reality of their dream state, and recognise that they are dreaming.

“The same cognitive ability was found to be demonstrated while awake by a person’s ability to think in a different way when it comes to solving problems.”

The study examined 68 participants aged between 18 and 25 who had experienced different levels of lucid dreaming, from never to several times a month. They were asked to solve 30 problems designed to test insight. Each problem consisted of three words and a solution word.

Each of the three words could be combined with the solution word to create a new compound word.

For example with the words ‘sand’, ‘mile’ and ‘age’, the linking word would be ‘stone’.

Results showed that frequent lucid dreamers solved 25 per cent more of the insight problems than the non-lucid dreamers.

Miss Shaw, who conducted the research as part of her undergraduate dissertation, said the ability to experience lucid dreams is something that can be learned. “We aren’t entirely sure why some people are naturally better at lucid dreaming than others, although it is a skill which can be taught,” said Hannah.

“For example you can get into the habit of asking yourself “is this a dream?”. If you do this during the day when you are awake and make it a habit then it can transfer to when you are in a dream.”

An extraordinary opportunity to study memory and post-traumatic stress disorder (PTSD) in a group of Air Transat passengers who experienced 30 minutes of unimaginable terror over the Atlantic Ocean in 2001 has resulted in the discovery of a potential risk factor that may help predict who is most vulnerable to PTSD.

The study, led by researchers at Baycrest Health Sciences, is published online this week in the journal Clinical Psychological Science – ahead of print publication. It is the first to involve detailed interviews and psychological testing in individuals exposed to the same life-threatening traumatic event. By necessity, other trauma studies involve heterogeneous events as experienced in different situations.

This opportunity was enhanced by the fact that one of the researchers, Dr. Margaret McKinnon, was a passenger on the plane. Heading off on her honeymoon in late August 2001, Dr. McKinnon’s flight departed Toronto for Lisbon, Portugal with 306 passengers and crew on board. Mid way over the Atlantic Ocean, the plane suddenly ran out of fuel. Everyone onboard was instructed to prepare for an ocean ditching, which included a countdown to impact, loss of on-board lighting and cabin de-pressurization. About 25 minutes into the emergency, the pilot located a small island military base in the Azores and glided the aircraft to a rough landing with no loss of life and few injuries.

“Imagine your worst nightmare – that’s what it was like,” said Dr. McKinnon, who initiated the study as a postdoctoral fellow at Baycrest’s Rotman Research Institute. She is now a clinician-scientist at St. Joseph’s Healthcare Hamilton and Associate Co-Chair of Research in the Department of Psychiatry and Behavioural Neurosciences at McMaster University in Hamilton.

“This wasn’t just a close call where your life flashes before your eyes in a split second and then everything is okay,” she said. The sickening feeling of “I’m going to die” lasted an excruciating 30 minutes as the plane’s systems shut down.

Following this incident, Dr. McKinnon and her colleagues at Baycrest – including Dr. Daniela Palombo (now a postdoctoral researcher at VA Boston Healthcare System and Boston University School of Medicine) and Dr. Brian Levine (senior scientist at Baycrest’s Rotman Research Institute and the University of Toronto) – recruited 15 passengers to participate in the Baycrest study. Using their knowledge of the moment-to-moment unfolding of events in this disaster, the researchers were able to probe both the quality and accuracy of passengers’ memories for the AT emergency in great detail along with two other events (Sept. 11, 2001 and a neutral event from the same time period) – and relate their findings to the presence or absence of PTSD in those passengers.

Not all passengers on Flight 236 went on to develop PTSD despite experiencing the same “single blow” traumatic event with the threat of imminent death.

The study produced two key findings. First, the Flight 236 passengers showed tremendously enhanced vivid memories of the plane emergency. Although the Baycrest team was not surprised by this, other research has suggested that memory for traumatic events is impoverished. Second, neither the vividness nor accuracy of memory related to who developed PTSD, but those with PTSD recalled a higher number of details external to the main event (i.e. details that were not specific in time, or were repetitions or editorial statements) compared to passengers who did not have PTSD and to healthy controls. This pattern was observed across all events tested, not just the traumatic event, suggesting that it is not just memory for the trauma itself that is related to PTSD, but rather how a person processes memory for events in general.

“What our findings show is that it is not what happened but to whom it happened that may determine subsequent onset of PTSD,” said Dr. Levine, senior author of the study.

This inability to shut out external or semantic details when recalling personally-experienced memories is related to mental control over memory recall, adding to a growing body of evidence that altered memory processing may be a vulnerability factor for PTSD.

A second study, in preparation for publication, involves functional brain imaging of 10 of the passengers from Air Transat Flight 236. The aim is to illuminate the brain mechanisms associated with exposure to this traumatic event.

A University of Queensland study has found no evidence of an increase in autism in the past 20 years, countering reports that the rates of autism spectrum disorders (ASDs) are on the rise.

The study, led by Dr Amanda Baxter from UQ’s Queensland Centre for Mental Health Research at the School of Population Health, was a first-of-its-kind analysis of research data from 1990 to 2010. 

Dr Baxter said she and her colleagues found that rates had remained steady, despite reports that the prevalence of ASDs was increasing.

“We found that the prevalence of ASDs in 2010 was one in 132 people, which represents no change from 1990,” Dr Baxter said.

“We found that better recognition of the disorders and improved diagnostic criteria explain much of the difference in study findings over time.”

Part of the Global Burden of Disease project, this is the largest study to systematically assess rates and disability caused by ASDs in the community, using data collected from global research findings in the past 20 years.

ASDs are chronic, disabling disorders that stem from problems with brain development.

They affect people from a young age and are among the world’s 20 most disabling childhood conditions.

The study shows that about 52 million children and adults around the globe meet diagnostic criteria for an ASD.

Dr Baxter said researchers hoped the study would help guide health policy and improve support for those with ASD and their families.

“As ASDs cause substantial lifelong health issues, an accurate understanding of the burden of these disorders can inform public health policy as well as help allocate necessary resources for education, housing and employment,” she said.

The study, a collaboration with the University of Leicester and the University of Washington’s Institute for Health Metrics and Evaluation, is published in Psychological Medicine journal.

Researchers at the Gladstone Institutes have shown that reducing brain levels of the protein tau effectively blocks the development of disease in a mouse model of Dravet syndrome, a severe intractable form of childhood epilepsy. This therapeutic strategy not only suppressed seizure activity and premature death, but also improved cognitive and behavioral abnormalities that can accompany this syndrome.

Previous studies from this group have shown that lowering tau levels reduces abnormal brain activity in models of Alzheimer’s disease, but this is the first demonstration that tau reduction may also be beneficial in intractable genetic epilepsy.

"It would really be wonderful if tau reduction turned out to be useful not only in Alzheimer’s disease, but also in other disabling neurological conditions for which there currently are no effective treatments," said senior author Lennart Mucke, MD, the director of the Gladstone Institute of Neurological Disease and a professor of Neurology and Neuroscience at the University of California, San Francisco. "We suspected that this approach might be beneficial in Dravet, but we couldn’t be sure because of the severity of this syndrome and the corresponding model. We are thrilled that our strategy was so effective, but a lot more work is needed to advance it into the clinic."

Dravet syndrome is one of the most challenging forms of childhood epilepsy, resulting from a specific genetic mutation that affects sodium channels in the brain. Frequent, relentless seizures are accompanied by cognitive impairments and behavioral problems similar to autism, and up to 20% of patients succumb to sudden death. Current treatments for Dravet syndrome are largely ineffective, making research into the disorder particularly urgent.

"I am especially excited about the improvements we observed in cognitive and behavioral dysfunctions because these abnormalities are particularly hard on the kids—and their parents," said first author Ania Gheyara, MD, PhD, a staff scientist at Gladstone who is also affiliated with the UCSF Department of Pathology. "Our hope is that this approach will be broadly applicable to many different types of epilepsy."

In the study, which was published online today in the Annals of Neurology, the scientists reduced the level of the protein tau by genetically engineering Dravet mouse models, “knocking out” the gene associated with tau production. The deletion of one copy of the gene resulted in substantial improvements in most symptoms, while deleting both copies eliminated them almost completely. This included a significant reduction in both spontaneous and heat-induced seizures. The latter were used to mimic the fever-related seizures that are often seen in the early stages of Dravet syndrome. Network activity in the brain was also normalized, providing additional support for the remarkable ability of tau reduction to suppress epileptic activity.

Additionally, tau reduction ameliorated the learning and memory deficits and behavioral abnormalities present in the Dravet mice, which may relate to the cognitive impairments and autism-like behaviors seen in the human condition.

"The next steps are to develop tau-lowering therapeutics that could be used in humans and to evaluate their safety and efficacy in preclinical studies," said Dr. Mucke, "objectives we are pursuing actively."

A team of researchers from the Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences have developed a new way of using electricity to open the blood-brain-barrier (BBB). The Vascular Enabled Integrated Nanosecond pulse (VEIN pulse) procedure consists of inserting minimally invasive needle electrodes into the diseased tissue and applying multiple bursts of nanosecond pulses with alternating polarity. It is thought that the bursts disrupt tight junction proteins responsible for maintaining the integrity of the BBB without causing damage to the surrounding tissue. This technique is being developed for the treatment of brain cancer and neurological disorders, such as Parkinson’s disease, and is set to appear in the upcoming issue of the journal TECHNOLOGY.

(Caption: Two, minimally invasive needle electrodes with 1 mm active length were spaced 4.0 mm apart and inserted into the right cerebral hemisphere 1.5 mm beneath the surface of the dura. A burst of 200, 500 ns duration square pulses of alternating polarity with a voltage-to-distance ratio of 250 V/cm were applied through the electrodes. In the case shown above, bursts were repeated once per second for 10 min. The extent of BBB disruption is shown by the dotted line surrounding Evans blue-albumin complex uptake on the gross brain slice preparation (left) and the corresponding fluorescent image (middle). Additionally, areas of BBB disruption appear as hyperintense (white) on the T1-weighted MRI exam, due to the uptake of a gadolinium-Evans blue tracer. Scale bar represents 5 mm. Credit: John H. Rossmeisl Jr., Neurology and Neurosurgery, Virginia-Maryland Regional College of Veterinary Medicine and Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences).

The BBB is a network of tight junctions that normally acts to protect the brain from foreign substances by preventing them from leaking out of blood vessels. However, it also limits the effectiveness of drugs to treat brain disease. Temporarily opening the BBB is a way to ensure that drugs can still be effective.

For the treatment of brain cancer, “VEIN pulses could be applied at the same time as biopsy or through the same track as the biopsy probe in order to mitigate damage to the healthy tissue by limiting the number of needle insertions,” says Rafael V. Davalos, Ph.D, director of the Bioelectromechanical Systems Laboratory at Virginia Tech.

Additionally, the group shows that VEIN pulses can be applied without causing muscle contractions, which may dislodge the electrodes and require the use of a neuroblocker and general anesthesia. According to Christopher B. Arena, Ph.D., co-lead author on the paper with Paulo A. Garcia, Ph.D. and Michael B. Sano, Ph.D., “the fact that the pulses alternate in polarity helps to avoid unwanted, electrically induced movement. Therefore, it could be possible to perform this procedure without using a neuroblocker and with patients under conscious sedation. This is similar to how deep brain stimulation is implemented clinically to treat Parkinson’s disease.”

The team now plans to translate the technology into clinical applications through a university spin-out company, VoltMed, Inc.