Neuroscience

Using auditory or tactile stimulation, Sensory Substitution Devices (SSDs) provide representations of visual information and can help the blind “see” colors and shapes. SSDs scan images and transform the information into audio or touch signals that users are trained to understand, enabling them to recognize the image without seeing it.

Currently SSDs are not widely used within the blind community because they can be cumbersome and unpleasant to use. However, a team of researchers at the Hebrew University of Jerusalem have developed the EyeMusic, a novel SSD that transmits shape and color information through a composition of pleasant musical tones, or “soundscapes.” A new study published in Restorative Neurology and Neuroscience reports that using the EyeMusic SSD, both blind and blindfolded sighted participants were able to correctly identify a variety of basic shapes and colors after as little as 2-3 hours of training.

Most SSDs do not have the ability to provide color information, and some of the tactile and auditory systems used are said to be unpleasant after prolonged use. The EyeMusic, developed by senior investigator Prof. Amir Amedi, PhD, and his team at the Edmond and Lily Safra Center for Brain Sciences (ELSC) and the Institute for Medical Research Israel-Canada at the Hebrew University, scans an image and uses musical pitch to represent the location of pixels. The higher the pixel on a vertical plane, the higher the pitch of the musical note associated with it. Timing is used to indicate horizontal pixel location. Notes played closer to the opening cue represent the left side of the image, while notes played later in the sequence represent the right side. Additionally, color information is conveyed by the use of different musical instruments to create the sounds: white (vocals), blue (trumpet), red (reggae organ), green (synthesized reed), yellow (violin); black is represented by silence.

“This study is a demonstration of abilities showing that it is possible to encode the basic building blocks of shape using the EyeMusic,” explains Prof. Amir Amedi. “Furthermore, the success in associating color to musical timbre holds promise for facilitating the representation of more complex shapes.” 

In addition to successfully identifying shapes and colors, users in the new EyeMusic study indicated they found the SSD’s soundscapes to be relatively pleasant and potentially tolerable for prolonged use. “In soundscapes generated from images,” notes Prof. Amedi, “there is a tendency for adjacent frequencies to be played together. Using a semitone western scale would then generate sounds that are perceived as highly dissonant. Therefore, to generate more pleasant soundscapes, we used the pentatonic musical scale that generates less dissonance when adjacent notes are played together.”

While this new study shows that the EyeMusic can enable the visually impaired to extract visual shape and color information using auditory soundscapes of objects, researchers feel that this device also holds great promise for the field of visual rehabilitation in general. By providing additional color information, the EyeMusic can help facilitate object recognition and scene segmentation, while the pleasant soundscapes offer the potential of prolonged use.

“There is evidence suggesting that the brain is organized as a task-machine and not as a sensory machine. This strengthens the view that SSDs can be useful for visual rehabilitation, and therefore we suggest that the time may be ripe for turning part of the SSD spotlight back on practical visual rehabilitation,” Prof. Amedi adds. “In the future, it would be intriguing to test whether the use of naturalistic sounds, like music and human voice, can facilitate learning and brain processing relying on the developed neural networks for music and human voice processing.”

Additionally, the researchers hope the EyeMusic can become a tool for future neuroscience research. “It would be intriguing to explore the plastic changes associated with learning to decode color information for auditory timbre in the congenitally blind, who never experience color in their life. The utilization of the EyeMusic and its added color information in the field of neuroscience could facilitate exploring several questions in the blind with the potential to expand our understanding of brain organization in general,” concludes Prof. Amedi.

A demonstration, “EyeMusic: Hearing colored shapes” is available from the AppStore.

All creatures great and small, including fruitflies, need sleep. Researchers have surmised that sleep – in any species — is necessary for repairing proteins, consolidating memories, and removing wastes from cells. But, really, sleep is still a great mystery.

Image caption: An alpha subunit of the nicotinic acetylcholine receptor accounts for the rye mutant phenotype. Expression pattern of redeye (green). Credit: Amita Sehgal and Mi Shi, PhD, Perelman School of Medicine, University of Pennsylvania

The timing of when we sleep versus are awake is controlled by cells in tune with circadian rhythms of light and dark. Most of the molecular components of that internal clock have been worked out. On the other hand, how much we sleep is regulated by another process called sleep homeostasis, however little is known about its molecular basis.

In a study published in eLIFE, Amita Sehgal, PhD, professor of Neuroscience at the Perelman School of Medicine, University of Pennsylvania, and colleagues, report a new protein involved in the homeostatic regulation of sleep in the fruitfly, Drosophila. Sehgal is also an investigator with the Howard Hughes Medical Institute (HHMI).

The researchers conducted a screen of mutant flies to identify short-sleeping individuals and found one, which they dubbed redeye. These mutants show a severe reduction in the amount of time they slumber, sleeping only half as long as normal flies. While the redeye mutants were able to fall asleep, they would wake again in only a few minutes.

The team found that the redeye gene encodes a subunit of the nicotinic acetylcholine receptor. This type of acetylcholine receptor consists of multiple protein subunits, which form an ion channel in the cell membrane, and, as the name implies, also binds to nicotine.  Although acetylcholine signaling — and cigarette smoking — typically promote wakefulness, the particular subunit studied in the eLIFE paper is required for sleep in Drosophila.

Levels of the redeye protein in the fly oscillate with the cycles of light and dark and peak at times of daily sleep. Normally, the redeye protein is expressed at times of increasing sleep need in the fly, right around the afternoon siesta and at the time of night-time sleep. From this, the team concluded that the redeye protein promotes sleep and is a marker for sleepiness – suggesting that redeye signals an acute need for sleep, and then helps to maintain sleep once it is underway.

In addition, cycling of the redeye protein is independent of the circadian clock in normal day:night cycles, but depends on the sleep homeostat. The team concluded this because redeye protein levels are upregulated in short-sleeping mutants as well as in wild-type animals following sleep deprivation. And, mutant flies had normal circadian rhythms, suggesting that their sleep problems were the result of disrupted sleep/wake homeostasis.

Ultimately the team wants to use the redeye gene to locate sleep homeostat neurons in the brain. “We propose that the homeostatic drive to sleep increases levels of the redeye protein, which responds to this drive by promoting sleep,” says Sehgal. Identification of molecules that reflect sleep drive could lead to the development of biomarkers for sleep, and may get us closer to revealing the mystery of the sleep homeostat.

Your memory is a wily time traveler, plucking fragments of the present and inserting them into the past, reports a new Northwestern Medicine® study. In terms of accuracy, it’s no video camera.

Rather, the memory rewrites the past with current information, updating your recollections with new experiences. 

Love at first sight, for example, is more likely a trick of your memory than a Hollywood-worthy moment.

“When you think back to when you met your current partner, you may recall this feeling of love and euphoria,” said lead author Donna Jo Bridge, a postdoctoral fellow in medical social sciences at Northwestern University Feinberg School of Medicine. “But you may be projecting your current feelings back to the original encounter with this person.”

The study is published Feb. 5 in the Journal of Neuroscience.

This the first study to show specifically how memory is faulty, and how it can insert things from the present into memories of the past when those memories are retrieved. The study shows the exact point in time when that incorrectly recalled information gets implanted into an existing memory.

To help us survive, Bridge said, our memories adapt to an ever-changing environment and help us deal with what’s important now.

“Our memory is not like a video camera,” Bridge said. “Your memory reframes and edits events to create a story to fit your current world. It’s built to be current.”

All that editing happens in the hippocampus, the new study found. The hippocampus, in this function, is the memory’s equivalent of a film editor and special effects team.

For the experiment, 17 men and women studied 168 object locations on a computer screen with varied backgrounds such as an underwater ocean scene or an aerial view of Midwest farmland. Next, researchers asked participants to try to place the object in the original location but on a new background screen. Participants would always place the objects in an incorrect location.

For the final part of the study, participants were shown the object in three locations on the original screen and asked to choose the correct location. Their choices were: the location they originally saw the object, the location they placed it in part 2 or a brand new location.

“People always chose the location they picked in part 2,” Bridge said. “This shows their original memory of the location has changed to reflect the location they recalled on the new background screen. Their memory has updated the information by inserting the new information into the old memory.”

Participants took the test in an MRI scanner so scientists could observe their brain activity. Scientists also tracked participants’ eye movements, which sometimes were more revealing about the content of their memories – and if there was conflict in their choices — than the actual location they ended up choosing.   

The notion of a perfect memory is a myth, said Joel Voss, senior author of the paper and an assistant professor of medical social sciences and of neurology at Feinberg.

“Everyone likes to think of memory as this thing that lets us vividly remember our childhoods or what we did last week,” Voss said. “But memory is designed to help us make good decisions in the moment and, therefore, memory has to stay up-to-date. The information that is relevant right now can overwrite what was there to begin with.”

Bridge noted the study’s implications for eyewitness court testimony. “Our memory is built to change, not regurgitate facts, so we are not very reliable witnesses,” she said.

A caveat of the research is that it was done in a controlled experimental setting and shows how memories changed within the experiment. “Although this occurred in a laboratory setting, it’s reasonable to think the memory behaves like this in the real world,” Bridge said.

Studies have shown that certain pesticides can increase people’s risk of developing Parkinson’s disease. Now, UCLA researchers have found that the strength of that risk depends on an individual’s genetic makeup, which, in the most pesticide-exposed populations, could increase a person’s chance of developing the debilitating disease two- to six-fold.

In an earlier study, published January 2013 in Proceedings of the National Academy of Sciences, the UCLA team discovered a link between Parkinson’s and the pesticide benomyl, a fungicide that has been banned by the U.S. Environmental Protection Agency. That study found that benomyl prevents the enzyme aldehyde dehydrogenase (ALDH) from converting aldehydes — organic compounds that are highly toxic to dopamine cells in the brain — into less toxic agents, thereby contributing to the risk of Parkinson’s.

For the current study, UCLA researchers tested a number of additional pesticides and found 11 that also inhibit ALDH and increase the risk of Parkinson’s — and at levels much lower than they are currently being used, said the study’s lead author, Jeff Bronstein, a professor of neurology and director of the movement disorders program at UCLA.

Bronstein said the team also found that people with a common genetic variant of the ALDH2 gene are particularly sensitive to the effects of ALDH-inhibiting pesticides and are two to six times more likely to develop Parkinson’s when exposed to these pesticides than those without the variant.

The results of the new epidemiological study appear Feb. 5 in the online issue of Neurology, the medical journal of the American Academy of Neurology.

"We were very surprised that so many pesticides inhibited ALDH and at quite low concentrations — concentrations that were way below what was needed for the pesticides to do their job," Bronstein said. "These pesticides are pretty ubiquitous and can be found on our food supply. They are used in parks and golf courses and in pest control inside buildings and homes. So this significantly broadens the number of people at risk."

The study compared 360 patients with Parkinson’s disease in three agriculture-heavy Central California counties and 816 people from the same area who did not have Parkinson’s. The researchers focused their analyses on individuals with ambient exposures to pesticides at work and at home, using information from the California Department of Pesticide Regulation.

In the previous PNAS study, Bronstein and his team had determined the mechanism that leads to increased risk. Exposure to pesticides starts a cascade of cellular events, preventing ALDH from keeping a lid on the aldehyde DOPAL, a toxin that naturally occurs in the brain. When ALDH does not detoxify DOPAL sufficiently, it accumulates, damages neurons and increases an individual’s risk of developing Parkinson’s.

"ALDH inhibition appears to be an important mechanism by which these environmental toxins contribute to Parkinson’s pathogenesis, especially in genetically vulnerable individuals," said study author Beate Ritz, a professor of epidemiology at UCLA’s Fielding School of Public Health. "This suggests several potential interventions to reduce Parkinson’s occurrence or to slow its progression."

In the current study, the research team developed a lab test to determine which pesticides inhibited ALDH. They then found that those participants in the epidemiologic study who had a genetic variant in the ALDH gene were at increased risk of Parkinson’s when exposed to these pesticides. Just having the variant alone, however, did not increase risk of the disease, Bronstein noted.

"This report provides evidence for the relevance of ALDH inhibition in Parkinson’s disease pathogenesis, identifies pesticides that should be avoided to reduce the risk of developing Parkinson’s disease and suggests that therapies modulating ALDH enzyme activity or otherwise eliminating toxic aldehydes should be developed and tested to potentially reduce Parkinson’s disease occurrence or slow its progression, particularly for patients exposed to pesticides," the study states.

University of Queensland researchers have made a surprise discovery about how the brain plans movement that may lead to more targeted treatments for patients with Parkinson’s disease.

The discovery was made by UQ’s Queensland Brain Institute (QBI) researcher Professor Pankaj Sah in collaboration with neurologist Professor Peter Silburn and neurosurgeon Associate Professor Terry Coyne from the UQ Centre for Clinical Research.

Professor Sah said the team examined the brains of 10 patients with Parkinson’s disease while the patients were awake during deep brain stimulation surgery, and found more than one part of the brain is responsible for planning movement.

“This study aimed to improve understanding of how different parts of the brain are involved in planning movement and controlling gait,” Professor Sah said.

The team was particularly interested in a part of the brain stem known as the pedunculopontine nucleus (PPN), which lies in the deepest part of the brain.

The PPN has previously been targeted as a treatment point for people with advanced Parkinson’s disease who are unable to walk.

“To date, we have known that walking is generally controlled by the outer part of the brain known as the cortex,” Professor Sah said.

“When you decide to walk, the cortex sends signals to your brain stem which in turn signals the spinal cord to initiate movement.

“We have also known that neurons in the PPN are activated during limb movement, but our study has shown they were also activated when patients were simply thinking about walking.

“This is a complete surprise, because general thinking has been that movement planning takes place in the cortex, but this study indicates it might be happening in the brain stem as well.”

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting more than six million people globally, and about 1 in 350 Australians.

Professor Sah said improved understanding of how the brain plans movement could lead to more targeted treatments for people with Parkinson’s.

“The cells involved in these networks seem to be one type of cell, so when thinking about drug treatments for Parkinson’s, maybe we should be targeting these cells,” Professor Sah said.

All the patients treated with deep brain stimulation also recorded positive outcomes with improvements with gait, highlighting the importance of neuroscientists working with clinicians.

Findings of the research are published in the Nature Neuroscience journal.

Stanford researchers may have solved a riddle about the inner workings of the brain, which consists of billions of neurons, organized into many different regions, with each region primarily responsible for different tasks.

The various regions of the brain often work independently, relying on the neurons inside that region to do their work. At other times, however, two regions must cooperate to accomplish the task at hand. The riddle is this: what mechanism allows two brain regions to communicate when they need to cooperate yet avoid interfering with one another when they must work alone?

In a paper published today in Nature Neuroscience, a team led by Stanford electrical engineering professor Krishna Shenoy reveals a previously unknown process that helps two brain regions cooperate when joint action is required to perform a task.

“This is among the first mechanisms reported in the literature for letting brain areas process information continuously but only communicate what they need to,” said Matthew T. Kaufman, who was a postdoctoral scholar in the Shenoy lab when he co-authored the paper.

Read More →

Drugs that modify DNA structure may be beneficial for treating Alzheimer’s Disease

In a study published this week in Nature Neuroscience, Bess Frost, PhD, and co-authors, identify abnormal expression of genes, resulting from DNA relaxation, that can be detected in the brain and blood of Alzheimer’s patients.

The protein tau is involved in a number of neurodegenerative disorders, including Alzheimer’s disease. Previous studies have implicated DNA damage as a cause of neuron, or cell, death in Alzheimer’s patients. Given that DNA damage can change the structure of DNA within cells, the researchers examined changes in DNA structure in tau-induced neurodegeneration. They used transgenic flies and mice expressing human tau to show that DNA is more relaxed in tauopathy. They then identified that the relaxation of tightly wound DNA and resulting abnormal gene expression are central events that cause neurons to die in Alzheimer’s disease.

The authors write, “Our work suggests that drugs that modify DNA structure may be beneficial for treating Alzheimer’s Disease.” The authors recommend, “A greater understanding of the pathway of DNA relaxation in tauopathies will allow us to identify the optimal target and explore the therapeutic potential of epigenetic-based drugs.”

A multicenter research team led by Cedars-Sinai neurologist Nancy Sicotte, MD, an expert in multiple sclerosis and state-of-the-art imaging techniques, used a new, automated technique to identify shrinkage of a mood-regulating brain structure in a large sample of women with MS who also have a certain type of depression.

In the study, women with MS and symptoms of “depressive affect” – such as depressed mood and loss of interest – were found to have reduced size of the right hippocampus. The left hippocampus remained unchanged, and other types of depression – such as vegetative depression, which can bring about extreme fatigue – did not correlate with hippocampal size reduction, according to an article featured on the cover of the January 2014 issue of Human Brain Mapping.

The research supports earlier studies suggesting that the hippocampus may contribute to the high frequency of depression in multiple sclerosis. It also shows that a computerized imaging technique called automated surface mesh modeling can readily detect thickness changes in subregions of the hippocampus. This previously required a labor-intensive manual analysis of MRI images.

Sicotte, the article’s senior author, and others have previously found evidence of tissue loss in the hippocampus, but the changes could only be documented in manual tracings of a series of special high-resolution MRI images. The new approach can use more easily obtainable MRI scans and it automates the brain mapping process.

“Patients with medical disorders – and especially those with inflammatory diseases such as MS – often suffer from depression, which can cause fatigue. But not all fatigue is caused by depression. We believe that while fatigue and depression often co-occur in patients with MS, they may be brought about by different biological mechanisms. Our studies are designed to help us better understand how MS-related depression differs from other types, improve diagnostic imaging systems to make them more widely available and efficient, and create better, more individualized treatments for our patients,” said Sicotte, director of Cedars-Sinai’s Multiple Sclerosis Program and the Neurology Residency Program. She received a $506,000 grant from the National Multiple Sclerosis Society last year to continue this research.

The word “chaperone” refers to an adult who keeps teenagers from acting up at a dance or overnight trip. It also describes a type of protein that can guard the brain against its own troublemakers: misfolded proteins that are involved in several neurodegenerative diseases.

Researchers at Emory University School of Medicine have demonstrated that as animals age, their brains are more vulnerable to misfolded proteins, partly because of a decline in chaperone activity.

The researchers were studying a model of spinocerebellar ataxia, but the findings have implications for understanding other diseases, such as Alzheimer’s, Parkinson’s and Huntington’s. They also identified targets for potential therapies: bolstering levels of either a particular chaperone or a growth factor in brain cells can protect against the toxic effects of misfolded proteins.

The results were published this week in the journal Neuron.

Scientists led by Shihua Li, MD, and Xiao-Jiang Li, MD, PhD devised a system in which production of a misfolding-prone protein that causes a form of spinocerebellar ataxia can be triggered artificially in mice at various ages. Both Li’s are professors of human genetics at Emory University School of Medicine. The first author of the paper is BCDB graduate student Su Yang.

Spinocerebellar ataxia is an inherited neurodegenerative disease in which patients develop gait problems and a loss of coordination in mid-life, because of atrophy of the cerebellum. There are several types, each caused by a mutation in a different gene.

Most of the mutations that cause spinocerebellar ataxia involve an expansion of a “polyglutamine repeat" in a protein. Having the same protein building block (the amino acid glutamine) repeated dozens of times alters the protein’s function and makes it more likely to misfold and clump together. The misfolded proteins are toxic and interfere with the normal forms of the same protein.

Huntington’s disease is caused by a similar polyglutamine repeat. Misfolded proteins also play roles in Alzheimer’s and Parkinson’s, although their production is not driven by an inherited polyglutamine repeat in those diseases.

Li’s team was trying to distinguish between two possibilities. One was that the duration of mutant protein accumulation is important for disease severity; aging might allow more misfolded proteins to accumulate and become toxic over time.

Instead, the scientists observed that older animals develop disease more quickly after mutant protein production is triggered. The mutant protein accumulates more quickly in 9- and 14-month old mice than in 3-month old mice, suggesting that aged neurons are more vulnerable to the effects of the misfolded protein.

Chaperones are proteins whose job is to “prevent improper liaisons" between other proteins; they prevent the sticky regions of proteins from grabbing something they’re not supposed to. Li’s team identified a particular chaperone called Hsc70 whose activity declines with age in the brain, while others’ activity does not.

To confirm Hsc70’s importance, the researchers showed that boosting cells’ levels of Hsc70 can bolster their ability to cope with misfolded proteins. Injecting mice in the cerebellum with a virus that forces cells to make more Hsc70 can slow degeneration. The researchers found that the mutant protein interferes with production of a growth factor called MANF (mesenchephalic astrocyte-derived neurotrophic factor) in the cerebellum and that Hsc70 can prevent this interference. Injection of a virus that forces cells to make more MANF can also slow degeneration.

Potentially, small molecules that increase Hsc70 or MANF levels could be used for treating spinocerebellar ataxia, says Xiao-Jiang Li.

Researchers led by Marta Barrachina, Institute of Neuropathology of the Bellvitge Biomedical Research Institute (IDIBELL) have identified a new subgroup of patients suffering from schizophrenia characterized by motor disorders.

The study, which was conducted in collaboration with the research team Mairena Martin at the University of Castilla La Mancha at Ciudad Real and clinical researchers of the Health Park Sant Joan de Deu at Sant Boi de Llobregat, has been published in the online edition of the Journal of Psychiatric Research and was funded by the TV3 Marathon in its 2008 edition.

Schizophrenia is a serious mental illness. From a clinical point of view is considered grouping several diseases that are not well defined or characterized by biomarkers.

Barrachina team studies the A2A adenosine receptor, which is highly expressed in the basal ganglia at the central nervous system and is involved in the control of movement. Furthermore this protein inhibits the activity of dopamine D2 receptor, hyperactivated in schizophrenia patients and typical antipsychotics target.

"We studied the post- mortem brains of patients," explains Barrachina "and we found that 50% had very low levels of adenosine A2A receptor. Interestingly, when comparing these data with clinical information provided by the clinical investigators of the study, we note that these patients had motor disorders." "In addition, we identified an epigenetic mechanism associated with the decreased receptor expression."

According to the researcher, this finding allows to “identify a new subset of schizophrenia patients with motor disorders.”

Proposal for combined therapy

This study opens the door to a clinical trial, based on radioimage, which would detect the levels of this protein and identify these patients and also to confirm the results obtained in the postmortem brains of patients. Barrachina team proposes to apply a specific combination therapy of antipsychotics and agonists of A2A adenosine. “Thus, the activity of adenosine A2A receptor will be favoured, reducing the dose of antipsychotics.”

Assessing structural and functional changes in the brain may predict future memory performance in healthy children and adolescents, according to a study appearing January 29 in The Journal of Neuroscience. The findings shed new light on cognitive development and suggest MRI and other tools may one day help identify children at risk for developmental challenges earlier than current testing methods allow.

Working memory capacity — the ability to hold onto information for a short period of time — is one of the strongest predictors of future achievements in math and reading. While previous studies showed that MRI could predict current working memory performance in children, scientists were unsure if MRI could predict their future cognitive capacity.

In the current study, Henrik Ullman, Rita Almeida, PhD, and Torkel Klingberg, MD, PhD, at the Karolinska Institutet in Sweden evaluated the cognitive abilities of a group of healthy children and adolescents and measured each child’s brain structure and function using MRI. Based on the MRI data collected during this initial testing, the researchers found they could predict the children’s working memory performance two years later, a prediction that was not possible using the cognitive tests.

“Our results suggest that future cognitive development can be predicted from anatomical and functional information offered by MRI above and beyond that currently achieved by cognitive tests,” said Ullman, the lead author of the study. “This has wide implications for understanding the neural mechanisms of cognitive development.”

The scientists recruited 62 children and adolescents between the ages of 6 and 20 years to the lab, where they completed working memory and reasoning tests. They also received multiple MRI scans to assess brain structure and changes in brain activity as they performed a working memory task. Two years later, the group returned to the lab to perform the same cognitive tests.

Using a statistical model, the researchers evaluated whether MRI data obtained during the initial tests correlated with the children’s working memory performance during the follow-up visit. They found that while brain activity in the frontal cortex correlated with children’s working memory at the time of the initial tests, activity in the basal ganglia and thalamus predicted how well children scored on the working memory tests two years later.

“This study is another contribution to the growing body of neuroimaging research that yields insights into unraveling present and predicting future cognitive capacity in development,” said Judy Illes, PhD, a neuroethicist at the University of British Columbia. “However, the appreciation of this important new knowledge is simpler than its application to everyday life. How a child performs today and tomorrow relies on multiple positive and negative life events that cannot be assessed by today’s technology alone.”

A chemical that’s found in fruits and vegetables from strawberries to cucumbers appears to stop memory loss that accompanies Alzheimer’s disease in mice, scientists at the Salk Institute for Biological Studies have discovered. In experiments on mice that normally develop Alzheimer’s symptoms less than a year after birth, a daily dose of the compound—a flavonol called fisetin—prevented the progressive memory and learning impairments. The drug, however, did not alter the formation of amyloid plaques in the brain, accumulations of proteins which are commonly blamed for Alzheimer’s disease. The new finding suggests a way to treat Alzheimer’s symptoms independently of targeting amyloid plaques.

"We had already shown that in normal animals, fisetin can improve memory," says Pamela Maher, a senior staff scientist in Salk’s Cellular Neurobiology Laboratory who led the new study. "What we showed here is that it also can have an effect on animals prone to Alzheimer’s."

More than a decade ago, Maher discovered that fisetin helps protect neurons in the brain from the effects of aging. She and her colleagues have since—in both isolated cell cultures and mouse studies—probed how the compound has both antioxidant and anti-inflammatory effects on cells in the brain. Most recently, they found that fisetin turns on a cellular pathway known to be involved in memory.

"What we realized is that fisetin has a number of properties that we thought might be beneficial when it comes to Alzheimer’s," says Maher.

So Maher—who works with Dave Schubert, the head of the Cellular Neurobiology Lab—turned to a strain of mice that have mutations in two genes linked to Alzheimer’s disease. The researchers took a subset of these mice and, when they were only three months old, began adding fisetin to their food. As the mice aged, the researchers tested their memory and learning skills with water mazes. By nine months of age, mice that hadn’t received fisetin began performing more poorly in the mazes. Mice that had gotten a daily dose of the compound, however, performed as well as normal mice, at both nine months and a year old.

"Even as the disease would have been progressing, the fisetin was able to continue preventing symptoms," Maher says.

In collaboration with scientists at the University of California, San Diego, Maher’s team next tested the levels of different molecules in the brains of mice that had received doses of fisetin and those that hadn’t. In mice with Alzheimer’s symptoms, they found, pathways involved in cellular inflammation were turned on. In the animals that had taken fisetin, those pathways were dampened and anti-inflammatory molecules were present instead. One protein in particular—known as p35—was blocked from being cleaved into a shorter version when fisetin was taken. The shortened version of p35 is known to turn on and off many other molecular pathways. The results were published December 17, 2013, in the journal Aging Cell.

Studies on isolated tissue had hinted that fisetin might also decrease the number of amyloid plaques in Alzheimer’s affected brains. However, that observation didn’t hold up in the mice studies. “Fisetin didn’t affect the plaques,” says Maher. “It seems to act on other pathways that haven’t been seriously investigated in the past as therapeutic targets.”

Next, Maher’s team hopes to understand more of the molecular details on how fisetin affects memory, including whether there are targets other than p35.

"It may be that compounds like this that have more than one target are most effective at treating Alzheimer’s disease," says Maher, "because it’s a complex disease where there are a lot of things going wrong."

They also aim to develop new studies to look at how the timing of fisetin doses affect its influence on Alzheimer’s.

"The model that we used here was a preventive model," explains Maher. "We started the mice on the drugs before they had any memory loss. But obviously human patients don’t go to the doctor until they are already having memory problems." So the next step in moving the discovery toward the clinic, she says, is to test whether fisetin can reverse declines in memory once they have already appeared.

It has long been believed that a person with a concussion should stay awake or not sleep for more than a few hours at a time.

But there appears to be no medical evidence to support that idea, according to a study regarding the relationship between traumatic brain injury, also known as TBI, and sleepiness conducted by scientists at Barrow Neurological Institute at Phoenix Children’s Hospital and the University of Arizona College of Medicine – Phoenix.

"This translational research study lays the foundation for understanding the immediate impact of brain injury on a person’s physiology. In this case, substantial post-traumatic sleep occurred regardless of injury timing or severity," said Jonathan Lifshitz, director of the Translational Neurotrauma Program at Barrow Neurological Institute at Phoenix Children’s Hospital and an associate professor at the UA College of Medicine – Phoenix. "These studies explore sleep as an immediate response to TBI."

Traumatic brain injury is a major cause of death and disability throughout the world with little pharmacological treatment for the individuals who suffer from lifelong problems associated with TBI. Clinical studies have provided evidence to support the claim that brain injury contributes to chronic sleep disturbances as well as excessive daytime sleepiness. Clinical observations have reported excessive sleepiness immediately following traumatic brain injury. However; there is a lack of experimental evidence to support or refute the benefit of sleep following a brain injury.

"We know that some individuals after a traumatic brain injury become excessively sleepy and some cannot sleep at all. It is not well understood why this occurs as mechanisms of injury, and locations of injury are not always consistent between clinical phenotypes of normal sleep, hypersomnia and insomnia," said Matthew Troester, a neurologist and sleep specialist at Phoenix Children’s Hospital and a clinical assistant professor at the UA College of Medicine – Phoenix.

Lifshiz and his associates are breaking new ground with descriptions of sleep in the acute – or immediately after injury – state, where little is known clinically, Troester added.

"They demonstrate that the subjects slept immediately and similarly post-injury no matter the severity of the injury or time of day the injury occurred. This tells us that the brain is reacting to the injury in a very specific manner – not something we always see clinically – and, ultimately, this may help us better understand what the role of sleep is in brain injury" such as being restorative, protective or merely a consequence of the injury, he said. "It is an exciting beginning."

This initial study is phase one of the Post-Traumatic Sleep Study. Phase two is in the works. The research will look to provide medical evidence for sleeping after a concussion.

When you learn how to play the piano, first you have to learn notes, scales and chords and only then will you be able to play a piece of music. The same principle applies to speech and to reading, where instead of scales you have to learn the alphabet and the rules of grammar.

But how do separate small elements come together to become a unique and meaningful sequence?

It has been shown that a specific area of the brain, the basal ganglia, is implicated in a mechanism called chunking, which allows the brain to efficiently organise memories and actions. Until now little was known about how this mechanism is implemented in the brain.

In an article published today (Jan 26th) in Nature Neuroscience, neuroscientist Rui Costa, and his postdoctoral fellow, Fatuel Tecuapetla, both working at the Champalimaud Neuroscience Programme (CNP) in Lisbon, Portugal, and Xin Jin, an investigator at the Salk Institute, in San Diego, USA, reveal that neurons in the basal ganglia can signal the concatenation of individual elements into a behavioural sequence.

"We trained mice to perform gradually faster sequences of lever presses, similar to a person who is learning to play a piano piece at an increasingly fast pace." explains Rui Costa. "By recording the neural activity in the basal ganglia during this task we found neurons that seem to treat a whole sequence of actions as a single behaviour."

The basal ganglia encompass two major pathways, the direct and the indirect pathways. The authors found that although activity in these pathways was similar during the initiation of movement, it was rather different during the execution of a behavioural sequence.

"The basal ganglia and these pathways are absolutely crucial for the execution of actions. These circuits are affected in neural disorders, such as Parkinson or Huntington’s disease, in which learning of action sequences is impaired", adds Xin Jin.

The work published in this article “is just the beginning of the story”, says Rui Costa. The Neurobiology of Action laboratory at the CNP, a group of around 20 researchers headed by Rui Costa, will continue to study the functional organisation of the basal ganglia during learning and execution of action sequences. Earlier this year, Rui Costa was awarded a 2 million euro Consolidation Grant by the European Research Council to study the mechanism of Chunking.

From the world of nanotechnology we’ve gotten electronic skin, or e-skin, and electronic eye implants or e-eyes. Now we’re on the verge of electronic whiskers. Researchers with Berkeley Lab and the University of California (UC) Berkeley have created tactile sensors from composite films of carbon nanotubes and silver nanoparticles similar to the highly sensitive whiskers of cats and rats. These new e-whiskers respond to pressure as slight as a single Pascal, about the pressure exerted on a table surface by a dollar bill. Among their many potential applications is giving robots new abilities to “see” and “feel” their surrounding environment.

“Whiskers are hair-like tactile sensors used by certain mammals and insects to monitor wind and navigate around obstacles in tight spaces,” says the leader of this research Ali Javey, a faculty scientist in Berkeley Lab’s Materials Sciences Division and a UC Berkeley professor of electrical engineering and computer science. “Our electronic whiskers consist of high-aspect-ratio elastic fibers coated with conductive composite films of nanotubes and nanoparticles. In tests, these whiskers were 10 times more sensitive to pressure than all previously reported capacitive or resistive pressure sensors.”

Javey and his research group have been leaders in the development of e-skin and other flexible electronic devices that can interface with the environment. In this latest effort, they used a carbon nanotube paste to form an electrically conductive network matrix with excellent bendability. To this carbon nanotube matrix they loaded a thin film of silver nanoparticles that endowed the matrix with high sensitivity to mechanical strain.

“The strain sensitivity and electrical resistivity of our composite film is readily tuned by changing the composition ratio of the carbon nanotubes and the silver nanoparticles,” Javey says. “The composite can then be painted or printed onto high-aspect-ratio elastic fibers to form e-whiskers that can be integrated with different user-interactive systems.”

Javey notes that the use of elastic fibers with a small spring constant as the structural component of the whiskers provides large deflection and therefore high strain in response to the smallest applied pressures. As proof-of-concept, he and his research group successfully used their e-whiskers to demonstrate highly accurate 2D and 3D mapping of wind flow. In the future, e-whiskers could be used to mediate tactile sensing for the spatial mapping of nearby objects, and could also lead to wearable sensors for measuring heartbeat and pulse rate.

“Our e-whiskers represent a new type of highly responsive tactile sensor networks for real time monitoring of environmental effects,” Javey says. “The ease of fabrication, light weight and excellent performance of our e-whiskers should have a wide range of applications for advanced robotics, human-machine user interfaces, and biological applications.”

A paper describing this research has been published in the Proceedings of the National Academy of Sciences. The paper is titled “Highly sensitive electronic whiskers based on patterned carbon nanotube and silver nanoparticle composite films.” Javey is the corresponding author. Co-authors are Kuniharu Takei, Zhibin Yu, Maxwell Zheng, Hiroki Ota and Toshitake Takahashi.

Increased inflammation following an infection impairs the brain’s ability to form spatial memories – according to new research. The impairment results from a decrease in glucose metabolism in the brain’s memory centre, disrupting the neural circuits involved in learning and memory.

Inflammation has long been linked to disorders of memory like Alzheimer’s disease. Severe infections can also impair cognitive function in healthy elderly individuals. The new findings published in the journal Biological Psychiatry help explain why inflammation impairs memory and could spur the development of new drugs targeting the immune system to treat dementia.

In the first trial to image how inflammation impairs human memory, the team at Brighton and Sussex Medical School scanned 20 participants before and after either a benign salty water injection or typhoid vaccination, used to induce inflammation. Positron emission tomography (PET) was used to measure the effects of inflammation on the consumption of glucose in the brain and after each scan participants tested their spatial memory by performing a series of tasks in a virtual reality.

A reduction in glucose metabolism within the brain’s memory centre, known as the Medial Temporal Lobe (MTL), was seen following inflammation. Participants also performed less well in spatial memory tasks, an effect that appeared to be directly mediated by the change in MTL metabolism.

"We have known for some time that severe infections can lead to long-term cognitive impairment in the elderly. Infections are also a common trigger for acute decline in function in patients with dementia and Alzheimer’s disease," explains Dr Neil Harrison, a Wellcome Trust Intermediate Clinical Fellow at BSMS who led the study. "This study suggests that catching a cold or the flu, which leads to inflammation in the brain, could impair our memory."

Infections are unlikely to cause long-term detrimental impact in the young and healthy but the findings are of great significance in the elderly. The team now plan to investigate the role of inflammation in dementia, including insight into how acute infections such as influenza influence the rate of progression and decline.

"Our findings suggest that the brain’s memory circuits are particularly sensitive to inflammation and help clarify the association between inflammation and decline in dementia," says Dr Harrison. "If we can control levels of inflammation, we may be able to reduce the rate of decline in patients’ cognition."

Infants born prematurely are at elevated risk for cognitive, motor, and behavioral deficits — the severity of which was, until recently, almost impossible to accurately predict in the neonatal period with conventional brain imaging technology. But physicians may now be able to identify the premature infants most at risk for deficits as well as the type of deficit, enabling them to quickly initiate early neuroprotective therapies, by using highly reliable 3-D MRI imaging techniques developed by clinician scientists at The Research Institute at Nationwide Children’s Hospital. The imaging technique also facilitates early and repeatable assessments of these therapies to help clinicians and researchers determine whether neuroprotective treatments are effective in a matter of weeks, instead of the two to five years previously required.

The researchers — experts in brain imaging and anatomy — developed a protocol for using the special imaging technique to study the development of 10 brain tracts in these tiny patients, work published online January 24 in PLOS One. Colorful 3-D images of each tract revealed the connections of the segments to different parts of the brain or the spinal cord. Each of the 10 tracts is important for certain functions and abilities, such as language, movement or vision.

“Developing a reliable and reproducible methodology for studying the premature brain was crucial in order for us to get to the next step: assessing neuroprotective therapies,” said Nehal A. Parikh, DO, principal investigator in the Center for Perinatal Research at Nationwide Children’s and senior author on the paper. “Now that we have this protocol, we can improve the standard of care and evaluate efforts to promote brain health within 8 to 12 weeks of beginning the interventions. That way, we can quickly see what really works.”

The study tested a detailed approach to measuring brain structure in extremely low birth weight infants at term-equivalent age by comparing their diffusion tensor tractography (DTT) scans to those of healthy, full-term newborns. DTT is a special MRI technique that produces 3-D images and is able to detect the brain’s structure and more subtle injuries than earlier forms of the technology.

The research team is the first to confirm differences in the fibrous structure of the 10 tracts between healthy, full-term infant brains and those of premature babies. Although the imaging technology is regularly used in adults, the tiny head size and lack of benchmark measurements in healthy infants meant that the use of DTT in premature infants was previously uncharted territory. With the detailed technique developed by Dr. Parikh’s team, the images can now be reproducibly processed and reliably interpreted.

“This protocol opens the field to far greater use of the methodology for targeting and assessing therapies in these infants,” said Dr. Parikh, who also is an associate professor of pediatrics at The Ohio State University College of Medicine. “We already have studies underway using our DTT segmentation methodology to measure the effectiveness of early neuroprotective interventions, such as the use of breast milk or skin-to-skin contact while premature babies are in intensive care.”

As imaging technology continues to be refined, the goal of targeted therapies based on the specific region of the brain with a delay or injury will become reality, Dr. Parikh predicted.For example, if an infant’s DTT scan indicates an under-developed corticospinal tract — the region of the brain controlling motor ability — physicians could immediately begin proactive physical therapies with the baby instead of waiting until the delay manifests itself. A repeat DTT scan a few months after beginning the therapy could then detect whether the therapy is effectively improving the structure of that brain tract.

“Because cognitive and behavioral deficits cannot be diagnosed until school age, there is an urgent need for robust early prognostic biomarkers,” said Dr. Parikh. “Our work is an important step in this direction and will facilitate early testing of neuroprotective interventions.”

Researchers from Massachusetts Eye and Ear, Harvard Medical School, Massachusetts Institute of Technology and Massachusetts General Hospital have demonstrated, for the first time, that aspirin intake correlates with halted growth of vestibular schwannomas (also known as acoustic neuromas), a sometimes lethal intracranial tumor that typically causes hearing loss and tinnitus.

Image credit: Stanford School of Medicine/Oghalai Lab

Motivated by experiments in the Molecular Neurotology Laboratory at Mass. Eye and Ear involving human tumor specimens, the researchers performed a retrospective analysis of over 600 people diagnosed with vestibular schwannoma at Mass. Eye and Ear. Their research suggests the potential therapeutic role of aspirin in inhibiting tumor growth and motivates a clinical prospective study to assess efficacy of this well-tolerated anti-inflammatory medication in preventing growth of these intracranial tumors.

“Currently, there are no FDA-approved drug therapies to treat these tumors, which are the most common tumors of the cerebellopontine angle and the fourth most common intracranial tumors,” explains Konstantina Stankovic, M.D., Ph.D., who led the study. “Current options for management of growing vestibular schwannomas include surgery (via craniotomy) or radiation therapy, both of which are associated with potentially serious complications.”

The findings, which are described in the February issue of the journal Otology & Neurotology, were based on a retrospective series of 689 people, 347 of whom were followed with multiple magnetic resonance imaging MRI scans (50.3%). The main outcome measures were patient use of aspirin and rate of vestibular schwannoma growth measured by changes in the largest tumor dimension as noted on serial MRIs. A significant inverse association was found among aspirin users and vestibular schwannoma growth (odds ratio: 0.50, 95 percent confidence interval: 0.29-0.85), which was not confounded by age or gender.

“Our results suggest a potential therapeutic role of aspirin in inhibiting vestibular schwannoma growth,” said Dr. Stankovic, who is an otologic surgeon and researcher at Mass. Eye and Ear, Assistant Professor of Otology and Laryngology, Harvard Medical School (HMS), and member of the faculty of Harvard’s Program in Speech and Hearing Bioscience and Technology.

Neuroscientists from the University of Leicester, in collaboration with the Department of Neurosurgery at the University California Los Angeles (UCLA), are to reveal details of how the brain determines the timing at which neurons in specific areas fire to create new memories.

This research exploits the unique opportunity of recording multiple single-neurons in patients suffering from epilepsy refractory to medication that are implanted with intracranial electrodes for clinical reasons.

The study, which is to be published in the academic journal Current Biology, is the result of collaboration between Professor Rodrigo Quian Quiroga and Dr Hernan Rey at the Centre for Systems Neuroscience at the University of Leicester and Professor Itzhak Fried at UCLA.

The work follows up on the group’s research into what was dubbed the ‘Jennifer Aniston neurons’ – neurons in the hippocampus and its surrounding areas within the brain that specifically fire in an ‘abstract’ manner when we see or hear a certain concept  - such as a person, an animal or a landscape - that we recognise.

Professor Quian Quiroga said: “The firing of these neurons is relatively very late after the moment of seeing the picture, or hearing the person’s name, but is still very precise. These neurons also fire only when the pictures are consciously recognised and remain silent when they are not.

“Our research shows that there is a specific brain response that marks the timing of the firing of these neurons. This response shortly precedes the neuron’s firing and is only present for the consciously recognised pictures - being absent if the pictures were not recognised.

“This brain response thus reflects an activation that provides a temporal window for processing consciously perceived stimuli in the hippocampus and surrounding cortex. Given the proposed role of these neurons in memory formation, we argue that the brain response we found is a gateway for processing consciously perceived stimuli to form or recall memories.”

Dr Hernan Rey, first author of the study, added: “This time-keeping may indeed be critical for synchronizing and combining multisensory information involving different processing times. This, in turn, helps in creating a unified conceptual representation that can be used for memory functions.”

Professor Quian Quiroga’s work is specifically concerned with examining how information about the external world - what we see, hear and touch - is represented by neurons in the brain and how this leads to the creation of our own internal representations and memories.

For example, we can easily recognize a person in a fraction of a second, even when seen from different angles, with different sizes, colours, contrasts and under strikingly different conditions. But how neurons in the brain are capable of creating such an ‘abstract’ representation, disregarding basic visual details, is only starting to be known.

Setting the stage for possible advances in pain treatment, researchers at The Johns Hopkins University and the University of Maryland report they have pinpointed two molecules involved in perpetuating chronic pain in mice. The molecules, they say, also appear to have a role in the phenomenon that causes uninjured areas of the body to be more sensitive to pain when an area nearby has been hurt. A summary of the research will be published on Jan. 23 in the journal Neuron.

Image caption: Nerves in mouse skin that are actively responding to the painful stimulus capsaicin have been genetically engineered to glow green. Hairs appear in yellow. Credit: David Rini

"With the identification of these molecules, we have some additional targets that we can try to block to decrease chronic pain," says Xinzhong Dong, Ph.D., associate professor of neuroscience at the Johns Hopkins University School of Medicine and an early career scientist at Howard Hughes Medical Institute. "We found that persistent pain doesn’t always originate in the brain, as some had believed, which is important information for designing less addictive drugs to fight it."

Chronic pain that persists for weeks, months or years after an underlying injury or condition is resolved afflicts an estimated 20 to 25 percent of the population worldwide and about 116 million people in the U.S., costing Americans a total of $600 billion in medical interventions and lost productivity. It can be caused by everything from nerve injuries and osteoarthritis to cancer and stress.

In their new research, the scientists focused on a system of pain-sensing nerves within the faces of mice, known collectively as the trigeminal nerve. The trigeminal nerve is a large bundle of tens of thousands of nerve cells. Each cell is a long “wire” with a hub at its center; the hubs are grouped together into a larger hub. On one side of this hub, three smaller bundles of wires — V1, V2 and V3 — branch off. Each bundle contains individual pain-sensing wires that split off to cover a specific territory of the face. Signals are sent through the wires to the hubs of the cells and then travel to the spinal cord through a separate set of bundles. From the spinal cord, the signals are relayed to the brain, which interprets them as pain. 

When the researchers pinched the V2 branch of the trigeminal nerve for a prolonged period of time, they found that the V2 and V3 territories were extra sensitive to additional pain. This spreading of pain to uninjured areas is typical of those experiencing chronic pain, but it can also be experienced during acute injuries, as when a thumb is hit with a hammer and the whole hand throbs with pain.

To figure out why, the researchers studied pain-sensing nerves in the skin of mouse ears. The smaller branches of the trigeminal V3 reach up into the skin of the lower ear. But an entirely different set of nerves is responsible for the skin of the upper ear. This distinction allowed the researchers to compare the responses of two unrelated groups of nerves that are in close proximity to each other.

To overcome the difficulty of monitoring nerve responses, Dong’s team inserted a gene into the DNA of mice so that the primary sensory nerve cells would glow green when activated. The pain-sensing nerves of the face are a subset of these.

When skin patches were then bathed in a dose of capsaicin — the active ingredient in hot peppers — the pain-sensing nerves lit up in both regions of the ear. But the V3 nerves in the lower ear were much brighter than those of the upper ear. The researchers concluded that pinching the connected-but-separate V2 branch of the trigeminal nerve had somehow sensitized the V3 nerves to “overreact” to the same amount of stimulus. (Watch nerves light up in this video.)

Applying capsaicin again to different areas, the researchers found that more nerve branches coming from a pinched V2 nerve lit up than those coming from an uninjured one. This suggests that nerves that don’t normally respond to pain can modify themselves during prolonged injury, adding to the pain signals being sent to the brain.

Knowing from previous studies that the protein TRPV1 is needed to activate pain-sensing nerve cells, the researchers next looked at its activity in the trigeminal nerve. They showed it was hyperactive in injured V2 nerve branches and in uninjured V3 branches, as well as in the branches that extended beyond the hub of the trigeminal nerve cell and into the spinal cord.

Next, University of Maryland experts in the neurological signaling molecule serotonin, aware that serotonin is involved in chronic pain, investigated its role in the TRPV1 activation study. The team, led by Feng Wei, M.D., Ph.D., blocked the production of serotonin, which is released from the brain stem into the spinal cord, and found that TRPV1 hyperactivity nearly disappeared.

Says Dong: “Chronic pain seems to cause serotonin to be released by the brain into the spinal cord. There, it acts on the trigeminal nerve at large, making TRPV1 hyperactive throughout its branches, even causing some non-pain-sensing nerve cells to start responding to pain. Hyperactive TRPV1 causes the nerves to fire more frequently, sending additional pain signals to the brain.”