Neuroscience

The information carried by the electrical activity of neurons is a mixture of stored memories, environmental circumstances, and current state of mind, scientists have found in a study of laboratory rats. The findings, which appear in the journal PLoS Biology, offer new insights into the neurobiological processes that give rise to knowledge and memory recall.

The study was conducted by Eduard Kelemen, a former graduate student and post-doctoral associate at the State University of New York (SUNY) Downstate Medical Center, and André Fenton, a professor at New York University’s Center for Neural Science and Downstate Medical Center. Kelemen is currently a postdoctoral fellow at University of Tuebingen in Germany.

The idea that recollection is not merely a replay of our stored experiences dates back to Plato. He believed that memory retrieval was, in fact, a much more intricate process—a view commonly accepted by today’s cognitive psychologists and couched in the theory of constructive recollection. The theory posits that during memory retrieval, information across different experiences may combine during recall to form a single experience. Such a process may explain the prevalence of false memories. For example, studies have shown that people mistakenly recalled seeing a school bus in a movie if the bus was mentioned after they watched the movie.

In addition, other scholarship has shown that a subject’s mindset can also influence the retrieved information. For example, looking at a house from the perspective of a homebuyer or a burglar leads to different recollections—potential purchasers may recall the house’s leaky roof while would-be burglars may remember where the jewelry is kept.

But while the psychological contours of retrieval are well-documented, very little is known about the neural activity that underlies this process.

With this in mind, Fenton and Kelemen centered their study on the neurophysiological processes rats employ as they solve problems that require memory retrieval. To do so, they employed techniques developed during the last two decades. These involve monitoring the electrical activity of neurons in the rats’ hippocampus—the part of the brain used to encode new memories and retrieve old ones. By spotting certain types of neuronal activity, researchers have historically been able to perform what amounts to a mind reading exercise to decode what the rat is thinking and even comprehend the specifics of the rats’ memory retrieval.

In their experiments, Fenton and Kelemen tested the viability of a concept, “cross-episode retrieval”— stimulating the brain activity in a given circumstance that was also activated in a previous, distinctive experience.

“Such cross-episode expression of past activity can create opportunities for generating novel associations and new information that was never directly experienced,” the authors wrote.

To test their hypotheses, rats were placed in a stable, circular arena, then in a rotating, circular arena of the same size, followed by a return to the stable arena. In the rotating arena condition, the surface turned slowly, making it necessary for the rat to think about its location either in terms of the rotating floor or in terms of the stationary room.

Overall, the results showed district neural activity between the stable and rotating conditions. However, during the rotating task, the researchers intermittently observed “cross-episode retrieval”—that is, at times, neurons expressed patterns of electrical activity under the rotating-arena condition that were similar to those activity patterns that were used in the stable-arena condition. Notably, cross-episode retrieval occurred more frequently when the angular position of the rotating arena was about to complete a full rotation and return to the same position as in the stable condition, demonstrating that retrieval is influenced by the environment.

To show that cross-episode retrieval was influenced by current state of mind, Fenton and Kelemen took advantage of an earlier finding from their experiments: during the arena rotation, neural activity switches between signaling the rat’s location in the stationary room and the rat’s location on the rotating arena floor. Cross-episode retrieval was also more likely when neuronal activity represented the position of the rat in the stationary room than when it represented positions that rotate with the arena. This showed that retrieval is influenced by internal cognitive variables that are encoded by hippocampal discharge—i.e., a state of mind.

“These experiments demonstrate novel, key features of constructive human episodic memory in rat hippocampal discharge,” explained Fenton, “and suggest a neurobiological mechanism for how experiences of different events that are separate in time can nonetheless comingle and recombine in the mind to generate new information that can sometimes amount to valuable, creative insight and knowledge.”

Clinical trials of drug treatments for neurological diseases such as Alzheimer’s and Parkinson’s often fail because the animal studies that preceded them were poorly designed or biased in their interpretation, according to a new study from an international team of researchers. More stringent requirements are needed to assess the significance of animal studies before testing the treatments in human patients, the researchers say.

The team — led by John Ioannidis, MD, DSc, a professor of medicine at the Stanford University School of Medicine and an expert in clinical trial design — assessed the results of more than 4,000 animal studies in 160 meta-analyses of potential treatments for neurological disorders from Alzheimer’s disease, Parkinson’s disease, stroke, spinal-cord injury and a form of multiple sclerosis. (A meta-analysis is a study that compiles and assesses information and conclusions from many independent experiments of a treatment, or intervention, for a particular condition.).

They determined that only eight of the 160 studies of potential treatments yielded the statistically significant, unbiased data necessary to support advancing the treatment to clinical trials. In contrast, 108 of the treatments were deemed at least somewhat effective at the time they were published.

Ioannidis and his collaborators at the University of Edinburgh in Scotland and the University of Ioannina School of Medicine in Greece say that animal studies of potential interventions can be made more efficient and reliable by increasing average sample size, being aware of statistical bias, publishing negative results and making all the results of all experiments on the effectiveness of a particular treatment — regardless of their outcome — freely accessible to scientists.

"Some researchers have postulated that animals may not be good models for human diseases," said Ioannidis. "I don’t agree. I think animal studies can be useful and perfectly fine. The problem is more likely to be related to the selective availability of information about the studies conducted on animals." Although the researchers focused here on neurological disorders, they believe it is likely that similar bias exists in animal studies of other types of disorders.

Ioannidis, who directs the Stanford Prevention Research Center, is the senior author of the research, published online in PLoS Biology on July 16. Lecturer Konstantinos Tsilidis, PhD, and postgraduate fellow Orestis Panagiotou, MD, of the University of Ioannina share lead authorship of the study. Panagiotou is currently a researcher at the National Cancer Institute’s Division of Cancer Epidemiology and Genetics.

Ioannidis is known for his efforts to strengthen the way that research is planned, carried out and reported. He was called “one of the world’s foremost experts on the credibility of medical research” in a profile published in The Atlantic magazine in 2010. He outlined some of the problems he observed in a 2005 essay in PLoS-Medicine titled, “Why most published research findings are false.” The essay is one of the most-downloaded articles in the history of the Public Library of Science, according to the journal’s media relations office.

For the new study, Ioannidis and his colleagues evaluated results in a database of the thousands of animal studies compiled over the years through the CAMARADES initiative (Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies), led by professor Malcolm MacLeod, PhD, from the University of Edinburgh, who is also a co-author of the study.

The team compared the number of experiments in the meta-analyses that would have been expected to yield positive results (based on their predicted statistical power) with the actual number of experiments with published positive results. The difference was striking: 919 expected versus the 1,719 that were published, implying that either negative results were not published, or that the results of the experiments were interpreted too optimistically.

"We saw that it was very common for these interventions to have published evidence that they would work," said Ioannidis. "It was extremely common to have results that suggest they would be effective in humans."

Furthermore, nearly half (46 percent) of the 160 meta-analyses showed evidence of small-study effects — a term used to describe the fact that a small study using fewer numbers of animals is more likely to find the intervention more effective than a larger study with many animals.

Ioannidis speculated that a reluctance to publish negative findings (that is, those that conclude that a particular intervention did not work any better than the control treatment) and a perhaps unconscious desire on the part of researchers to find a promising treatment has colored the field of neurological research. Obscuring access to studies that conclude a particular treatment is ineffective, while also publishing positive results that are likely to be statistically flawed, tilts the perception toward the potential effectiveness of an intervention and encourages unwarranted human clinical trials.

"There are no standard rules that guide a decision to move from animal studies into human clinical trials," said Ioannidis, who also holds C.F. Rehnborg Professorship at Stanford. "Sometimes interventions are tested in humans with very little evidence that they may be effective. Of the 160 analyses we studied, only eight had what we would call strong evidence of potential effectiveness with no hint of bias in the preliminary animal studies. And of these eight, only two have given positive results in humans."

Ioannidis believes the development of consortiums of groups of researchers studying a particular intervention, coupled with the free sharing of all data about its effectiveness, or lack thereof, is a good first step in reducing bias in animal studies.

"Under the current conditions, only a tiny proportion of interventions that have published some promising results in animals have shown to be at all effective in humans. For example, while dozens of treatments on ischemic or hemorrhagic stroke seem to work in the animal literature, almost none of them have worked in humans," said Ioannidis. "It is hard to believe we could not improve upon that translation record. If we raise the bar for moving into human trials, centralize researchers’ efforts and make all results available, it will be much easier for researchers to know whether they have a potential winner, and it would increase the efficiency of human clinical trials enormously."

Premenopausal women who aren’t interested in sex and are unhappy about this reality have distinctive blood flow patterns in their brains in response to explicit videos compared to women with normal sexual function, researchers report.

A study of 16 women – six with normal sexual function and 10 with clear symptoms of dysfunction – showed distinct differences in activation of brain regions involved in making and retrieving memories, and determining how attentive they are to their response to sexual stimuli, researchers report in the journal Fertility and Sterility.

Up to 20 percent of women may have this form of sexual dysfunction, called hypoactive sexual desire disorder, for which there are no proven therapies, said Dr. Michael P. Diamond, Chairman of the Department of Obstetrics and Gynecology at the Medical College of Georgia at Georgia Regents University.

Researchers hope that a clearer understanding of physiological differences in these women will provide novel therapy targets as well as a method to objectively assess therapies, said Diamond, the study’s senior author.

"There are site-specific alterations in blood flow in the brains of individuals with hypoactive sexual disorders versus those with normal sexual function," Diamond said. "This tells me there is a physiologic means of assessing hypoactive sexual desire and that as we move forward with therapeutics, whether it’s counseling or medications, we can look to see whether changes occur in those regions."

Viagra, developed in the 1990s as way to increase the heart rate of sick babies, was approved by the Food and Drug Administration in 1998 to also treat male impotence, a major cause of sexual dysfunction. While several more options for men have been developed since, no FDA-approved options are available for women experiencing hypoactive sexual desire, Diamond said. He notes that a possible critical flaw in developing and evaluating therapies for women may be the inability to objectively measure results, other than with a woman’s self-reporting of its impact on sexual activity.

Years ago, Diamond, a reproductive endocrinologist, became frustrated by the inability to help these women. In fact, many women did not bother discussing the issue with their physicians, possibly because it’s an awkward problem with no clear solutions, he said.

While still at Wayne State University, he and his colleagues began looking for objective measures of a woman’s sexual response, identifying sexually explicit film clips, then using functional magnetic resonance imaging, which measures real-time brain activation in response to a stimulus, to look at responses.

Their latest study links acquired hypoactive sexual desire disorder to a distinct pattern of blood flow in the brain, with significant activation of cortical structures involved in attention and reflection about emotion and mental state. Researchers noted that paying more attention to response to sexual stimuli already is implicated in sexual dysfunction. They also note activation of the anterior cingulate gyrus, an area involved in a broad range of emotions including homeostasis, pain, depression, and apathy. Another key area was the amygdala, which has a central role in processing emotion, learning, and memory.

Women with normal sexual function showed significantly greater activation of areas such as the right thalamus - a sort of relay station for handling sensory and motor input – that also plays a role in sexual arousal. They also experienced activation of the parahippocampal gyrus, involved in making and recalling memories. Interestingly, this area has been found to be more significantly activated in women with surgical menopause receiving hormone therapy.

Diamond notes that the official diagnosis of the sexual disorder requires distress regarding persistent disinterest in sex. Study participants were heterosexual, in stable relationships and had previously viewed sexually explicit images. Those with sexual dysfunction had a mean age of 37 versus 29 in the control group. Part of assessing blood flow patterns included also measuring baseline responses to neutral videos.

Next steps include taking these measurements in a larger number of women and beginning to use brain blood flow patterns to assess therapies, Diamond said.

Whether you’re reading the paper or thinking through your schedule for the day, chances are that you’re hearing yourself speak even if you’re not saying words out loud. This internal speech — the monologue you “hear” inside your head — is a ubiquitous but largely unexamined phenomenon. A new study looks at a possible brain mechanism that could explain how we hear this inner voice in the absence of actual sound.

In two experiments, researcher Mark Scott of the University of British Columbia found evidence that a brain signal called corollary discharge — asignal that helps us distinguish the sensory experiences we produce ourselves from those produced by external stimuli — plays an important role in our experiences of internal speech.

The findings from the two experiments are published in Psychological Science, a journal of the Association for Psychological Science.

Corollary discharge is a kind of predictive signal generated by the brain that helps to explain, for example, why other people can tickle us but we can’t tickle ourselves. The signal predicts our own movements and effectively cancels out the tickle sensation.

And the same mechanism plays a role in how our auditory system processes speech. When we speak, an internal copy of the sound of our voice is generated in parallel with the external sound we hear.

“We spend a lot of time speaking and that can swamp our auditory system, making it difficult for us to hear other sounds when we are speaking,” Scott explains. “By attenuating the impact our own voice has on our hearing — using the ‘corollary discharge’ prediction — our hearing can remain sensitive to other sounds.”

Scott speculated that the internal copy of our voice produced by corollary discharge can be generated even when there isn’t any external sound, meaning that the sound we hear when we talk inside our heads is actually the internal prediction of the sound of our own voice.

If corollary discharge does in fact underlie our experiences of inner speech, he hypothesized, then the sensory information coming from the outside world should be cancelled out by the internal copy produced by our brains if the two sets of information match, just like when we try to tickle ourselves.

And this is precisely what the data showed. The impact of an external sound was significantly reduced when participants said a syllable in their heads that matched the external sound. Their performance was not significantly affected, however, when the syllable they said in their head didn’t match the one they heard.

These findings provide evidence that internal speech makes use of a system that is primarily involved in processing external speech, and may help shed light on certain pathological conditions.

“This work is important because this theory of internal speech is closely related to theories of the auditory hallucinations associated with schizophrenia,” Scott concludes.

A new study from neuroscientists at the Wayne State University School of Medicine provides the first novel insights into the neural origins of hot flashes in menopausal women in years. The study may inform and eventually lead to new treatments for those who experience the sudden but temporary episodes of body warmth, flushing and sweating.

The paper, “Temporal Sequencing of Brain Activations During Naturally Occurring Thermoregulatory Events,” by Robert Freedman, Ph.D., professor of psychiatry and behavioral neurosciences, founder of the Behavioral Medicine Laboratory and a member at the C.S. Mott Center for Human Growth and Development, and his collaborator, Vaibhav Diwadkar, Ph.D., associate professor of psychiatry and behavioral neurosciences, appears in the June issue of Cerebral Cortex, an Oxford University Press journal.

“The idea of understanding brain responses during thermoregulatory events has spawned many studies where thermal stimuli were applied to the skin. But hot flashes are unique because they are internally generated, so studying them presents unique challenges,” said Freedman, the study’s principal investigator. “Our participants had to lie in the MRI scanner while being heated between two body-size heating pads for up to two hours while we waited for the onset of a hot flash. They were heroic in this regard and the study could not have been conducted without their incredible level of cooperation.”

“Menopause and hot flashes are a significant women’s health issue of widespread general interest,” Diwadkar added. “However, understanding of the neural origins of hot flashes has remained poor. The question has rarely been assessed with in vivo functional neuroimaging. In part, this paucity of studies reflects the technical limitations of objectively identifying hot flashes while symptomatic women are being scanned with MRI. Nothing like this has been published because this is a very difficult study to do.”

During the course of a single year, 20 healthy, symptomatic postmenopausal women ages 47 to 58 who reported six or more hot flashes a day were scanned at the School of Medicine’s Vaitkevicius Imaging Center, located in Detroit’s Harper University Hospital.

The researchers collected skin conductance levels to identify the onset of flashes while the women were being scanned. Skin conductance is an electrical measure of sweating. The women were connected to a simple circuit passing a very small current across their chests, Diwadkar said. Changes in levels allowed researchers to identify a hot flash onset and analyze the concurrently acquired fMRI data to investigate the neural precedents and correlates of the event.

The researchers focused on regions like the brain stem because its sub regions, such as the medullary and dorsal raphe, are implicated in thermal regulation, while forebrain regions, such as the insula, have been implicated in the personal perception of how someone feels. They showed that activity in some brain areas, such as the brain stem, begins to rise before the actual onset of the hot flash.

“Frankly, evidence of fMRI-measured rise in the activity of the brain stem even before women experience a hot flash is a stunning result. When this finding is considered along with the fact that activity in the insula only rises after the experience of the hot flash, we gain some insight on the complexity of brain mechanisms that mediate basic regulatory functions,” Diwadkar said.

These results point to the plausible origins of hot flashes in specific brain regions. The researchers believe it is the first such demonstration in academic literature.

They are now evaluating the network-based interactions between the brain regions by using more complex modeling of the fMRI data. “We think that our study highlights the value of using well-designed fMRI paradigms and analyses in understanding clinically relevant questions,” Diwadkar said.

The researchers also are exploring possibilities for integrating imaging with treatment to examine whether specific pharmacotherapies for menopause might alter regional brain responses.

The trajectory of amyloid plaque buildup—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study published online July 15 in the Journal of Neurobiology of Aging.

Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. “Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,” said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.

Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.

Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.

“It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,” Dr. Davatzikos said. “This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.”

The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analyzed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analyzing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.

Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).

Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.   

A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.

“This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,” said Dr Davatzikos. “The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.”

A little bit of learned fear is a good thing, keeping us from making risky, stupid decisions or falling over and over again into the same trap. But new research from neuroscientists and molecular biologists at USC shows that a missing brain protein may be the culprit in cases of severe over-worry, where the fear perseveres even when there’s nothing of which to be afraid.

In a study appearing the week of July 15 in the Proceedings of the National Academy of Sciences, the researchers examined mice without the enzymes monoamine oxidase A and B (MAO A/B), which sit next to each other in a human’s genetic code as well as on that of mice. Prior research has found an association between deficiencies of these enzymes in humans and developmental disabilities along the autism spectrum, such as clinical perseverance, the inability to change or modulate actions along with social context.

“These mice may serve as an interesting model to develop interventions to these neuropsychiatric disorders,” said University Professor and senior author Jean Shih, Boyd & Elsie Welin Professor of Pharmacology and Pharmaceutical Sciences at the USC School of Pharmacy and the Keck School of Medicine of USC. “The severity of the changes in the MAO A/B knockout mice compared to MAO A knockout mice supports the idea that the severity of autistic-like features may be correlated to the amounts of monoamine levels, particularly at early developmental stages.”

Shih is a world leader in understanding the neurobiological and biochemical mechanisms behind such behaviors as aggression and anxiety. In this latest study, Shih and her co-investigators — including lead author Chanpreet Singh, a USC doctoral student at the time of the research who is now at the California Institute of Technology (Caltech), and Richard Thompson, USC University Professor Emeritus and Keck Professor of Psychology and Biological Sciences at the USC Dornsife College of Letters, Arts and Sciences — expanded their past research on MAO A/B, which regulates neurotransmitters known as monoamines, including serotonin, norepinephrine and dopamine.

Comparing mice without MAO A/B with their wild-type littermates, the researchers found significant differences in how the mice without MAO A/B processed fear and other types of learning. Mice without MAO A/B and wild mice were put in a new, neutral environment and given a mild electric shock. All mice showed learned fear the next time they were tested in the same environment, with the MAO A/B knockout mice displaying a greater degree of fear.

But while wild mice continued to explore other new environments freely after the trauma, mice without the MAO A/B enzymes generalized their phobia to other contexts — their fear spilled over onto places where they should have no reason to be afraid.

“The neural substrates processing fear in the brain is very different in these mice,” Singh said. “Enhanced learning in the wrong context is a disorder and is exemplified by these mice. Their brain is not letting them forget. In a survival issue, you need to be able to forget things.”

The mice without MAO A and MAO B also learned eye-blink conditioning much more quickly than wild mice, which has also been noted in autistic patients but not in mice missing only one of these enzymes.

Importantly, the mice without MAO A/B did not display any differences in learning for spatial skills and object recognition, the researchers found, “but in their ability to learn an emotional event, the [MAO A/B knockout mice] are very different than wild types,” Singh said.

He continued: “When both enzymes are missing, it significantly increases the levels of neurotransmitters, which causes developmental changes, which leads to differential expression of receptors that are very important for synaptic plasticity — a measure of learning — and to behavior that is quite similar to what we see along the autism spectrum.”

We take it for granted that our thoughts are in constant turnover. Metaphors like “stream of consciousness” and “train of thought” imply steady, continuous motion. But is there a mechanism inside our heads that drives this? Is there something compelling our attention to move on to new ideas instead of dwelling in the same spot forever?

A research team led by Dr Matthew Johnson in the School of Psychology at The University of Nottingham Malaysia Campus (UNMC) may have discovered part of the answer. They have pinpointed an effect that makes people turn their attention to something new rather than dwelling on their most recent thoughts. The research, which has been published in the academic journal Psychological Science, could have implications for studying disorders like autism and ADHD.

Dr Johnson said: “We have discovered a very promising paradigm. The effect is strong and replicates easily – you could demonstrate it in any psychology lab in the world. The work is still in its early stages but I think this could turn out to be a very important part of our understanding of how and why our thoughts work the way they do.

The paper “Foraging for Thought: An Inhibition-of-Return-Like Effect Resulting From Directing Attention Within Working Memory” sheds new light on what makes us turn our attention to things we haven’t recently thought rather than ones we have. It was carried out in collaboration with Yale University, Princeton University, The Ohio State University, and Manhattanville College.

The “inhibition of return” effect is well-established in visual attention. At certain time scales, people are slower to turn their thoughts back to a location they have just paid attention to. They are much quicker to focus on a new location. Some have interpreted this effect as a “foraging facilitator,” a process that encourages organisms to visit new locations over previously visited ones when exploring a new environment or performing a visual search.

However, in this new study, the researchers weren’t focusing on visual search, but on the process of thought itself. Participants were shown either two words or two pictures, and when the items disappeared, they were instructed to turn their attention briefly to one of the items they were just shown and ignore the other. Immediately afterwards they were asked to identify either the item they had just thought about, or the one they had ignored. For both pictures and words the participants were quicker to react to the item they had ignored.

Dr Johnson said: “The effect was shocking. When we began we expected to find the exact opposite – that thinking about something will make it easier to identify. We were initially disappointed – but when the effect was replicated over multiple experiments we realised we were onto something new and exciting.”

Critically, the effect is temporary; on a later memory test participants remembered attended items better than ignored ones.

Dr Johnson said: “That’s important. If thinking about things made us worse at remembering them long-term, it would make no sense for real-world survival. That’s why we think we’ve tapped into something fundamental about how we think in the moment – a possible mechanism keeping our thoughts moving onto new things, and not getting stuck.”

The researchers have more experiments planned to explore this effect. They say the new task could have implications for studying disorders like autism and ADHD, where attention may persist too long or move on too easily, as well as conditions with more general cognitive impairments, such as schizophrenia and ageing-related dementia.

Future studies planned also include applying cognitive neuroscience techniques to determine the effect’s underlying neural foundations.

Ninety-somethings seem to be getting smarter. Today’s oldest people are surviving longer, and thankfully appear to have sharper minds than the people reaching their 90s 10 years ago.

Kaare Christensen, head of the Danish Aging Research Center at the University of Southern Denmark in Odense, and colleagues found Danish people born in 1915 were about a third more likely to live to their 90s than those born in 1905, and were smarter too.

During research, which spanned 12 years and involved more than 5000 people, the team gave nonagenarians born in 1905 and 1915 a standard test called a “mini-mental state examination”, and cognitive tests designed to pick up age-related changes. Not only did those born in 1915 do better at both sets of tests, more of them also scored top marks in the mini-mental state exam.

It’s a landmark study, says Marcel Olde Rikkert, head of the Alzheimer’s centre at Radboud University Nijmegen Medical Centre in the Netherlands. It is scientifically rigorous, it invited all over 90-year-olds in Denmark to participate, and it also overturns our ingrained views of old age, he says.

Getting better all the time

"The outcome underlines that ageing is malleable," Olde Rikkert says, adding that cognitive function can actually be a lot better than people would assume until a very high age.

"It’s motivating that people, their lifestyles, and their environments can contribute a lot to the way they age," he says, though he cautions that not everything is in our own hands and help is still needed for those with dementia or those who do experience cognitive decline as they age.

Improved education played a part in the changes, says Christensen. But the study does not disentangle the individual effects of the numerous things that could be responsible for the improvements. “The 1915 cohort had a number of factors on their side – they experienced better living and working conditions, they had radio, TV and newspapers earlier in their lives than those born 10 years before,” he says.

Tellingly, there was no difference in the physical test results between the two groups. The authors say this “suggests changes in the intellectual environment rather than in the physical environment are the basis for the improvement”.

By comparing the human genome to the genomes of 34 other mammals, Australian scientists have described an unexpectedly high proportion of functional elements conserved through evolution.

Less than 1.5% of the human genome is devoted to conventional genes, that is, encodes for proteins.  The rest has been considered to be largely junk.  However, while other studies have shown that around 5-8% of the genome is conserved at the level of DNA sequence, indicating that it is functional, the new study shows that in addition much more, possibly up to 30%, is also conserved at the level of RNA structure.

DNA is a biological blueprint that must be copied into another form before it can be actualised. Through a process known as ‘transcription’, DNA is copied into RNA, some of which ‘encodes’ the proteins that carry out the biological tasks within our cells. Most RNA molecules do not code for protein, but instead perform regulatory functions, such as determining the ways in which genes are expressed.

Like infinitesimally small Lego blocks, the nucleic acids that make up RNA connect to each other in very specific ways, which force RNA molecules to twist and loop into a variety of complicated 3D structures.

Dr Martin Smith and Professor John Mattick, from Sydney’s Garvan Institute of Medical Research, devised a method for predicting these complex RNA structures – more accurate than those used in the past – and applied it to the genomes of 35 different mammals, including bats, mice, pigs, cows, dolphins and humans. At the same time, they matched mutations found in the genomes with consistent RNA structures, inferring conserved function. Their findings are published in Nucleic Acids Research, now online.

“Genomes accumulate mutations over time, some of which don’t change the structure of associated RNAs. If the sequence changes during evolution, yet the RNA structure stays the same, then the principles of natural selection suggest that the structure is functional and is required for the organism,” explained Dr Martin Smith.

“Our hypothesis is that structures conserved in RNA are like a common template for regulating gene expression in mammals – and that this could even be extrapolated to vertebrates and less complex organisms.”

“We believe that RNA structures probably operate in a similar way to proteins, which are composed of structural domains that assemble together to give the protein a function.”

“We suspect that many RNA structures recruit specific molecules, such as proteins or other RNAs, helping these recruited elements to bond with each other. That’s the general hypothesis at the moment – that non-coding RNAs serve as scaffolds, tethering various complexes together, especially those that control genome organization and expression during development.”

“We know that many RNA transcripts are associated with diseases and developmental conditions, and that they are differentially expressed in distinct cells.”

“Our structural predictions can serve as an annotative tool to help researchers understand the function of these RNA transcripts.”

“That is the first step – the next is to describe the structures in more detail, figure out exactly what they do in the cell, then work out how they relate to our normal development and to disease.”

Pioneering experiments back in 1982 by Tasaki and Iwasa at the NIH revealed that action potentials in neurons are more than just the electrical blips that physiologists readily amplify and record. These so-called “spikes” are in fact multi-modal signalling packages that include mechanical and thermal disturbances propagating down the axon at their own rates. Nobel Laureate Francis Crick published a paper that same year, in which he postulated potential mechanisms that would explain twitching in dendritic spines, adding to an emerging picture of a brain more vibrant and motile than had been previously imagined. More recently, researchers have developed diffusion-based MRI methods, like diffusion tensor imaging (DTI), to trace the trajectories of axons, and perhaps more intriguingly, determine their directional polarity. Working at the EPFL in Switzerland, Denis Le Bihan and his co-workers have been using diffusional MRI in slightly different way. They now appear to be able to directly measure neuronal activity from the subtle movements of membranes, the water within them, and in the extracellular space around them. Their work, just published in PNAS, provides a much needed conceptual shift away from currently established, but typically nebulous, ideas regarding neurovascular coupling of brain activity to blood flow.

Present-day imaging methods, like blood oxygen level-dependent (BOLD) MRI, are only indirectly and remotely related to the cortical activity they often claim to measure. In 2006, Le Bihan reported a water “phase transition” response that preceded the neurovascular response normally detected by functional MRI. He attributed the changes in water diffusion to previously established effects involving membrane expansion and cell swelling secondary to activity. At the biophysical level, interpreting action potentials as phase transitions is a little off the beaten path from traditional neurobiology, but it can be an informative approach when to trying to understand what might be going on when cells fire.

As biophysicist Gerald Pollack has previously pointed out, spikes may involve the propagation of the line of transition of water from the ordered phase, (as patterned by hydrophic interactions nucleated at the surfaces of membranes and proteins) to a disordered phase.
Traditionally, the so-called bound surface water only extends out a only a couple of molecules from the surface of nondiffusable features. That idea may need to be revisited in light of more recent understanding when attempting to account for the diffusion of water in axons. A decrease in water diffusion as measured by MRI may be in part explained by a decrease in extracellular space, and that has been suggested from experiments measuring intrinsic optical effects. The larger picture of water diffusion, however, is likely a bit more complicated than this.

In his new study, Le Bihan stimulated the forepaw of a rat and looked at responses in the somatosensory cortex. The key experiment was to infuse nitroprusside in attempt to inhibit neurovascular coupling. It is a tricky alteration because nitroprusside apparently has many diffuse effects. It can induce potent vasodilation, particularly on the vascular end (mainly the smaller venules), after it breaks down to produce nitric oxide. It is also a diamagnetic molecule, and each molecule releases five cyanide ions, which are presumably detoxified by the mitochondrial enzyme rhodanese. The experiments were done under isoflurane anesthesia, which also introduces a few uncertainties, particularly with regard to responses to different frequencies of forepaw stimulation.

If nitroprusside is indeed a realistic experimental proxy for neurovascular uncoupling, then the results of Le Bihan appear to show that the diffusion response is not of vascular origin, and that it is closely linked to neural activation. He found that the standard BOLD MRI responses were completely quenched under nitroprusside, whereas the diffusion MRI responses were only slightly suppressed. Local field potentials were also simultaneously measured and suggested at least, that the neuronal responses were also intact.

The work of Le Bihan indicates that diffusion-based MRI can be used to infer neural activity directly from the structural changes that affect the molecular displacements of water. The ability to use shape changes in neurons, astrocytes, or even spines, raises the question of whether these kinds of techniques might eventually be of use in creating larger scale, and more detailed, Brain Activity Maps (BAMs). I asked Konrad Kording, author on the recent theoretical paper which discussed the theoretical limits to MRI and other activity recording methods, whether methods that probe water movements might be applied to this end.

Kording observed that the spatial resolution of standard MRI is ultimately limited by the diffusion of water, but more importantly perhaps, the temporal resolution of all known MRI methods is nowhere near that required to create spike maps. None-the-less, detecting mechanical responses in the brain could provide many unique insights into function. For example, experiments using agents that dissolve the extracellular matrix, like the clot-busting drug TPA, result in more twitching, or vibration if you will, in dendritic spines. Other studies have shown that the greater the electrical drive on a spine, the less it tends to twitch or change size, particularly during periods of rapid development.

Similarly, sensory deprivations appear to increase these kinds of movements as neurons grow and reorganize connections. While these effects are far below that which could be detected by any large external method of MRI, new tools may permit us to access these newly-revealed activities. Diffusional MRI in particular, can be done with a little modification of the standard MRI procedure. For example, to determine directional diffusion parameters, or diffusion tensors, typically six gradients are used to measure three directional vectors. As these capabilities become more common, hopefully the results of Le Bihan can be further explored and verified.

A new study reveals that the representation of complex features in the brain may begin earlier—and play out in a more cumulative manner—than previously thought.

The finding represents a new view of how the brain creates internal representations of the visual world. “We are excited to see if this novel view will dominate the wider consensus” said senior author Dr. Miyashita, who is also Professor of Physiology at the University of Tokyo’s School of Medicine, “and also about the potential impact of our new computational principle on a wide range of views on human cognitive abilities.”

The brain recalls the patterns and objects we observe by developing distinct neuronal representations that go along with them (this is the same way it recalls memories). Scientists have long hypothesized that these neuronal representations emerge in a hierarchical process limited to the same cortical region in which the representations are first processed.

Because the brain perceives and recognizes the external world through these internal images, any new information about the process by which this takes place has the power to inform our understanding of related functions, including knowledge acquisition and memory.

However, studies attempting to uncover the functional hierarchy involved in the cortical process of visual stimuli have tried to characterize this hierarchy by analyzing the activity of single nerve cells, which are not necessarily correlated with neurons nearby, thus leaving these analyses lacking.

In a new study appearing in the 12 July issue of the journal Science, lead author Toshiyuki Hirabayashi and colleagues focus not on single neurons but instead on the relationship between neuron pairs, testing the possibility that the representation of an object in a single brain region emerges in a hierarchically lower brain area.

"I became interested in this work," said Dr. Hirabayashi, "because I was impressed by the elaborate neuronal circuitry in the early visual system, which is well-studied, and I wanted to explore the circuitry underlying higher-order visual processing, which is not yet fully understood."

Hirabayashi and colleagues analyzed nerve cell pairs in cortical areas TE and 36, the latter of which is hierarchically higher, in two adult macaques. After these animals looked at six sets of paired stimuli for several months to learn to associate related objects (a process that can lead to pair-coding neurons in the brain), the researchers recorded neuron responses in areas TE and 36 of both animals as they again performed this task.

The neurons exhibited pair association, but not where the researchers would have thought. “The most surprising result,” said senior author Dr. Yasushi Miyashita “was that the neuronal circuit that generated pair-association was found only in area TE, not in area 36.” Indeed, based on previous studies, which indicated that the number of pair-coding neurons in area TE is much smaller, the researchers would have expected the opposite.

During their study, Miyashita and other team members observed that in region TE of the macaque cortex, unit 1 neurons (or source neurons) provided input to unit 2 neurons (or target neurons), which—unlike unit 1 neurons—responded to both members of a stimulus pair.

"The representations generated in area TE did not reflect a mere random fluctuation of response patterns," explained Dr. Miyashita, "but rather, they emerged as a result of circuit processing inherent to that area of the brain."

In area 36, meanwhile, members of neuron pairs behaved differently; on average, unit 1 as well as unit 2 neurons responded to both members of a stimulus pair. Neurons in area 36 received input from area TE, but only from its unit 2 neurons.

Taken together, these findings lead the authors to hypothesize the existence of a hierarchical relationship between regions TE and 36, in which paired associations first established in the former region are propagated to the latter one. Here, area 36 represents the next level of a so-called feed forward hierarchy.

The work by Hirabayashi and colleagues suggests that the detailed representations of objects commonly observed in the brain are attained not by buildup of representations in a single area, but by emergence of these representations in a hierarchically prior area and their subsequent transfer to the brain region that follows. There, they become sufficiently prevalent for the brain to register. The work also reveals that the brain activity involved in recreating visual stimuli emerges in a hierarchically lower brain area than previously thought.

Moving forward, the Japanese research team has plans to expand upon this research, thus continuing to contribute to studies worldwide that aim to give scientists the best possible tools with which to obtain a dynamic picture of the brain. As a next step, the team hopes to further elucidate interactions between the various cortical microcircuits that operate in memory encoding. Dr. Miyashita has conjectured that these microcircuits are manipulated by a global brain network. Using the results of this latest study, he and colleagues are poised to further evaluate this assumption.

"It will also be important to weave the neuronal circuit mechanisms into a unified framework," said Dr. Hirabayashi," and to examine the effects of learning on these circuit organizations."

Equipped with their new view of cortical processing, the team also hopes to trace the causal chain of memory retrieval across different areas of the cortex. “I am excited by the recent development of genetic tools that will allow us to do this,” said Dr. Miyashita. A better understanding of object representations from one area of the brain to the next will shed even greater light on elusive aspects of this hierarchical organ.

Deep brain stimulation therapy blocks or modulates electrical signals in the brain to improve symptoms in patients suffering from movement disorders such as Parkinson’s disease, essential tremor and dystonia, but a new study suggests that several factors may cause electrical current to vary over time.

Led by Michele Tagliati, MD, director of Cedars-Sinai Medical Center’s Movement Disorders Program, the study identified variables that affect impedance – resistance in circuits that affect intensity and wavelength of electrical current. Doctors who specialize in programming DBS devices fine-tune voltage, frequency and other parameters for each patient; deviations from these settings may have the potential to alter patient outcomes.

“Deep brain stimulation devices are currently designed to deliver constant, steady voltage, and we believe consistency and reliability are critical in providing therapeutic stimulation. But we found that we cannot take impedance stability for granted over the long term,” said Tagliati, the senior author of a journal article that reveals the study’s findings.

“Doctors with experience in DBS management can easily make adjustments to compensate for these fluctuations, and future devices may do so automatically,” he added. “Although our study was not designed to link changes in impedance and voltage with clinical outcomes, we believe it is important for patients to have regular, ongoing clinic visits to be sure they receive a steady level of stimulation to prevent the emergence of side effects or the re-emergence of symptoms.”

Findings of the study – one of the largest of its kind and possibly the first to follow patients for up to five years – were published online ahead of print in Brain Stimulation. Researchers collected 2,851 impedance measurements in 94 patients over a period of six months to five years, evaluating fluctuations in individual patients and in individual electrodes. They looked at a variety of factors, including how long a patient had undergone treatment, the position of the implanted electrode, the side of the brain where the electrode was implanted, and even placement and function of contact positions along electrodes.

Medications usually are the first line of treatment for movement disorders, but if drugs fail to provide adequate relief or side effects are excessive, neurologists and neurosurgeons may supplement them with deep brain stimulation. Electrical leads are implanted in the brain, and an electrical pulse generator is placed near the collarbone. The device is then programmed with a remote, hand-held controller.

A collaborative formed by Autism Speaks, the world’s leading autism science and advocacy organization, has found full genome sequencing examining the entire DNA code of individuals with autism spectrum disorder (ASD) and their family members to provide the definitive look at the wide ranging genetic variations associated with ASD. The study published online today in American Journal of Human Genetics, reports on full genome sequencing on 32 unrelated Canadian individuals with autism and their families, participants in the Autism Speaks Autism Genetic Resource Exchange (AGRE). The results include both inherited as well as spontaneous or de novo, genetic alterations found in one half of the affected families sequenced.

This dramatic finding of genetic risk variants associated with clinical manifestation of ASD or accompanying symptoms in 50 percent of the participants tested is promising, as current diagnostic technology has only been able to determine a genetic basis in about 20 percent of individuals with ASD tested. The large proportion of families identified with genetic alterations of concern is in part due to the comprehensive and uniform ability to examine regions of the genome possible with whole genome sequencing missed in other lower resolution genome scanning approaches.

"From diagnosis to treatment to prevention, whole genome sequencing efforts like these hold the potential to fundamentally transform the future of medical care for people with autism," stated Autism Speaks Chief Science Officer and study co-author Robert Ring, Ph.D.

The study identified genetic variations associated with risk for ASD including de novo, X-linked and other inherited DNA lesions in four genes not previously recognized for ASD; nine genes previously determined to be associated with ASD risk; and eight candidate ASD risk genes. Some families had a combination of genes involved. In addition, risk alterations were found in genes associated with fragile X or related syndromes (CAPRIN1 and AFF2), social-cognitive deficits (VIP), epilepsy (SCN2A and KCNQ2) as well as NRXN1 and CHD7, which causes ASD-associated CHARGE syndrome.

“Whole genome sequencing offers the ultimate tool to advance the understanding of the genetic architecture of autism,” added lead author Dr. Stephen Scherer, senior scientist and director of the Centre for Applied Genomics at The Hospital for Sick Children (SickKids) and director of the McLaughlin Centre at the University of Toronto. “In the future, results from whole genome sequencing could highlight potential molecular targets for pharmacological intervention, and pave the way for individualized therapy in autism. It will also allow for earlier diagnosis of some forms of autism, particularly among siblings of children with autism where recurrence is approximately 18 per cent.”  

This $1 million collaboration of Autism Speaks, SickKids, BGI and Duke University piloted Autism Speaks’ initiative to generate the world’s largest library of sequenced genomes of individuals with ASD announced in late 2011. “As we continue to test more individuals and their family members from the AGRE cohort, we expect to discover and study additional genetic variants associated with autism. This collaboration will accelerate basic and translational research in autism and related developmental disabilities,” concluded Autism Speaks Vice President for Scientific Affairs Andy Shih, Ph.D. who oversees the collaboration, “and this collection of sequenced genomes will facilitate new collaborations engaging researchers around the world, and enable public and private entities to pursue pivotal research.”

In this pilot effort, a total of 99 individuals were tested, including the 32 individuals with ASD (25 males and seven females) and their two parents, as well as three members of one control family not on the autism spectrum.  Using families in the Autism Speaks AGRE collection, this Autism Speaks initiative will ultimately perform whole genome sequencing on more than 2,000 participating families who have two or more children on the autism spectrum. The data from the 10,000 AGRE participants will enable new research in the genomics of ASD, and significantly enhance the science and technology networks of Autism Speaks and its collaborators.

The idea that females are more resilient than males in responding to stress is a popular view, and now University at Buffalo researchers have found a scientific explanation. The paper describing their embargoed study will be published July 9 online, in the high-impact journal, Molecular Psychiatry.

“We have examined the molecular mechanism underlying gender-specific effects of stress,” says senior author Zhen Yan, PhD, a professor in the Department of Physiology and Biophysics in the UB School of Medicine and Biomedical Sciences. “Previous studies have found that females are more resilient to chronic stress and now our research has found the reason why.”

The research shows that in rats exposed to repeated episodes of stress, females respond better than males because of the protective effect of estrogen.

In the UB study, young female rats exposed to one week of periodic physical restraint stress showed no impairment in their ability to remember and recognize objects they had previously been shown. In contrast, young males exposed to the same stress were impaired in their short-term memory.

An impairment in the ability to correctly remember a familiar object signifies some disturbance in the signaling ability of the glutamate receptor in the prefrontal cortex, the brain region that controls working memory, attention, decision-making, emotion and other high-level “executive” processes.

Last year, Yan and UB colleagues published in Neuron a paper showing that repeated stress results in loss of the glutamate receptor in the prefrontal cortex of young males.

The current paper shows that the glutamate receptor in the prefrontal cortex of stressed females is intact. The findings provide more support for a growing body of research demonstrating that the glutamate receptor is the molecular target of stress, which mediates the stress response.

The stressors used in the experiments mimic challenging and stressful, but not dangerous, experiences that humans face, such as those causing frustration and feelings of being under pressure, Yan says.

By manipulating the amount of estrogen produced in the brain, the UB researchers were able to make the males respond to stress more like females and the females respond more like males.

“When estrogen signaling in the brains of females was blocked, stress exhibited detrimental effects on them,” explains Yan. “When estrogen signaling was activated in males, the detrimental effects of stress were blocked.

“We still found the protective effect of estrogen in female rats whose ovaries were removed,” says Yan. “It suggests that it might be estrogen produced in the brain that protects against the detrimental effects of stress.”

In the current study, Yan and her colleagues found that the enzyme aromatase, which produces estradiol, an estrogen hormone, in the brain, is responsible for female stress resilience. They found that aromatase levels are significantly higher in the prefrontal cortex of female rats.

“If we could find compounds similar to estrogen that could be administered without causing hormonal side effects, they could prove to be a very effective treatment for stress-related problems in males,” she says.

She notes that while stress itself is not a psychiatric disorder, it can be a trigger for the development of psychiatric disorders in vulnerable individuals.

Several human and animal studies have shown a relationship between a preference for highly sweet tastes and alcohol use disorders. Furthermore, the brain mechanisms of sweet-taste responses may share common neural pathways with responses to alcohol and other drugs. A new study using functional magnetic resonance imaging (fMRI) has found that recent drinking is related to the orbitofrontal-region brain response to an intensely sweet stimulus, a brain response that may serve as an important phenotype, or observable characteristic, of alcoholism risk.

Results will be published in the December 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"It has long-been known that animals bred to prefer alcohol also drink considerably greater quantities of sweetened water than do animals without this selective breeding for alcohol preference," explained David A. Kareken, deputy director of the Indiana Alcohol Research Center, a professor in the department of neurology at Indiana University School of Medicine, and corresponding author for the study. "More recently, it has become clear that animals bred to prefer the artificial sweetener, saccharin, also drink more alcohol. Although the data in humans are somewhat more variable, some studies do show that alcoholics, or even non-alcoholics with a family history of alcoholism, have a preference for unusually sweet tastes. Thus, while the precise reasons remain unclear, there does seem to be significant evidence suggesting some link between the rewarding properties of both sweet tastes and alcohol."

Kareken added that this is the first study to examine the extent to which regions of the brain’s reward system, as they respond to an intensely sweet taste, are related to human drinking patterns.

Kareken and his colleagues recruited 16 (12 males, 4 females) right-handed, non-treatment seeking, healthy volunteers with a mean age of 26 years from the community. All participants underwent a taste test using a range of sucrose concentrations, and their blood oxygen dependent (BOLD) activation was measured during an fMRI scan while receiving small squirts of either water or an intensely sweet mixture of sugar in water. All were asked about their drinking patterns.

"Our study was designed to determine which brain areas responded to sweet taste – as compared to plain water – and the extent to which these brain responses were related to subjects’ binge-drinking patterns, the number of alcoholic drinks subjects consumed per day when drinking," explained Kareken.

"In addition to ‘activating’ the brain’s gustatory or taste circuits, the sugared water also activated key elements of what neuroscientists consider to be part of the brain’s reward system, including the ventral striatum, amygdala, and parts of the orbitofrontal cortex – the inferior frontal lobe surface just above the eyes – that respond to ingested rewards," Kareken said. "We refer to these as ‘primary’ rewards, being distinct from secondary rewards, like money, which can be used to obtain primary rewards."

What the researchers found was that the response to this intensely sweet taste in the left orbitofrontal area correlated significantly with subjects’ drinking patterns.

"Specifically, the trend was such that those who drank more alcohol on drinking days had stronger left orbitofrontal responses to the intensely sweet water," said Kareken. "Subjects’ subjectively rated liking of the sweetened water also contributed to this relationship, so that both the brain response itself, as well as liking of the sugared water, collectively correlated with drinking behavior."

While previous human and animal research has noted this association between preferences for both sweet tastes and alcohol intoxication, Kareken believes that this is the first study to examine the human brain mechanism behind this association.

"While much more research needs to be done to truly understand the commonalities between sweet-liking and alcoholism, and while alcoholism itself is likely the product of several mechanisms, our findings may implicate a particular brain region that is more generally involved in coding for the value of ‘primary’ rewards such as pleasures," he said. "In a more practical sense, the findings are compelling evidence that the brain response to an intensely sweet taste may be used in future research to test for differences in the reward circuits of those at risk for alcoholism. This may be particularly useful since alcohol itself is not an easy drug to work with in this kind of human imaging, and since alcohol exposure is not ethically appropriate for use in all at-risk subjects, or in subjects trying to abstain from drinking."

A recent 3D-comparative analysis confirms the status of Homo floresiensis as a fossil human species

Ever since the discovery of the remains in 2003, scientists have been debating whether Homo floresiensis represents a distinct Homo species, possibly originating from a dwarfed island Homo erectus population, or a pathological modern human. The small size of its brain has been argued to result from a number of diseases, most importantly from the condition known as microcephaly.

Based on the analysis of 3-D landmark data from skull surfaces, scientists from Stony Brook University New York, the Senckenberg Center for Human Evolution and Palaeoenvironment, Eberhard-Karls Universität Tübingen, and the University of Minnesota provide compelling support for the hypothesis that Homo floresiensis was a distinct Homo species.

The study, titled “Homo floresiensis contextualized: a geometric morphometric comparative analysis of fossil and pathological human samples,” is published in the July 10 edition of PLOS ONE.

The ancestry of the Homo floresiensis remains is much disputed.
The critical questions are: Did it represent an extinct hominin species? Could it be a Homo erectus population, whose small stature was caused by island dwarfism?

Or, did the LB1 skull belong to a modern human with a disorder that resulted in an abnormally small brain and skull? Proposed possible explanations include microcephaly, Laron Syndrome or endemic hypothyroidism (“cretinism”).

The scientists applied the powerful methods of 3-D geometric morphometrics to compare the shape of the LB1 cranium (the skull minus the lower jaw) to many fossil humans, as well as a large sample of modern human crania suffering from microcephaly and other pathological conditions. Geometric morphometrics methods use 3D coordinates of cranial surface anatomical landmarks, computer imaging, and statistics to achieve a detailed analysis of shape.

This was the most comprehensive study to date to simultaneously evaluate the two competing hypotheses about the status of Homo floresiensis.

The study found that the LB1 cranium shows greater affinities to the fossil human sample than it does to pathological modern humans. Although some superficial similarities were found between fossil, LB1, and pathological modern human crania, additional features linked LB1exclusively with fossil Homo. The team could therefore refute the hypothesis of pathology.

“Our findings provide the most comprehensive evidence to date linking the Homo floresiensis skull with extinct fossil human species rather than with pathological modern humans. Our study therefore refutes the hypothesis that this specimen represents a modern human with a pathological condition, such as microcephaly,” stated the scientists.

In the constant cross talk between our brain and our gut, two gut hormones are already known to tell the brain when we have had enough to eat. New research suggests that boosting levels of these hormones simultaneously may be an effective new weapon in the fight against obesity.

Dr Shu Lin, Dr Yan-Chuan Shi and Professor Herbert Herzog, from Sydney’s Garvan Institute of Medical Research, have shown that when mice are injected with PYY3-36 and PP, they eat less, gain less fat, and tend not to develop insulin-resistance, a precursor to diabetes. At the same time, the researchers have shown that the hormones stimulate different nerve pathways, ultimately, however, affecting complementary brain regions. Their findings are now published online in the journal Obesity.

While the double-barreled approach may seem like a no-brainer, the strongly enhanced effect seen was by no means inevitable. In the complex world of neuroscience, two plus two does not always make four.

Drug companies are in the process of conducting pre-clinical trials to examine the separate effects of boosting the hormones PYY3-36 and PP. Until now, there is no research to indicate the detailed molecular interactions that might occur when they are boosted in tandem.

When used together, the hormones independently, yet with combined force, reduce the amount of neuropeptide Y (NPY) produced by the brain, a powerful neurotransmitter that affects a variety of things including appetite, mood, heart rate, temperature and energy levels.

Each hormone also communicates with a different part of the arcuate nucleus in the hypothalamus, a region of the brain where signals can cross the normally impermeable blood / brain barrier. The stimulated regions then produce other neuronal signals deep within the hypothalamus, bringing about a powerful combined effect.

“There are many factors that influence appetite control – and we now realise that there won’t be a single molecular target, or a single drug, that will be effective,” said Dr Yan-Chuan Shi.

“It will be important for drug companies to try different combinations of targets, to see which combinations are most potent, and at the same time have no side effects, or at least minimal side effects.”

“At the moment, the only effective tool against obesity is surgery. Drug companies have so far failed to produce an effective drug without unacceptable side effects, such as mood disorders, nausea or cardiovascular problems.”

Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease that rapidly atrophies the muscles, leading to complete paralysis. Despite its high profile — established when it afflicted the New York Yankees’ Lou Gehrig — ALS remains a disease that scientists are unable to predict, prevent, or cure.

Although several genetic ALS mutations have been identified, they only apply to a small number of cases. The ongoing challenge is to identify the mechanisms behind the non-genetic form of the disease and draw useful comparisons with the genetic forms.

Now, using samples of stem cells derived from the bone marrow of non-genetic ALS patients, Prof. Miguel Weil of Tel Aviv University’s Laboratory for Neurodegenerative Diseases and Personalized Medicine in the Department of Cell Research and Immunology and his team of researchers have uncovered four different biomarkers that characterize the non-genetic form of the disease. Each sample shows similar biological abnormalities to four specific genes, and further research could reveal additional commonalities. “Because these genes and their functions are already known, they give us a specific direction for research into non-genetic ALS diagnostics and therapeutics,” Prof. Weil says. His initial findings were reported in the journal Disease Markers.

Giving in to stress

To hunt for these biomarkers, Prof. Weil and his colleagues turned to samples of bone marrow collected from ALS patients. Though more difficult to collect than blood, bone marrow’s stem cells are easy to isolate and grow in a consistent manner. In the lab, he used these cells as cellular models for the disease. He ultimately discovered that cells from different ALS patients shared the same abnormal characteristics of four different genes that may act as biomarkers of the disease. And because the characteristics appear in tissues that are related to ALS — including in muscle, brain, and spinal cord tissues in mouse models of genetic ALS — they may well be connected to the degenerative process of the disease in humans, he believes.

Searching for the biological significance of these abnormalities, Prof. Weil put the cells under stress, applying toxins to induce the cells’ defense mechanisms. Healthy cells will try to fight off threats and often prove quite resilient, but ALS cells were found to be overwhelmingly sensitive to stress, with the vast majority choosing to die rather than fight. Because this is such an ingrained response, it can be used as a feature for drug screening for the disease, he adds.

The hunt for therapeutics

Whether these biomarkers are a cause or consequence of ALS is still unknown. However, this finding remains an important step towards uncovering the mechanisms of the disease. Because these genes have already been identified, it gives scientists a clear direction for future research. In addition, these biomarkers could lead to earlier and more accurate diagnostics.

Next, Prof. Weil plans to use his lab’s high-throughput screening facility — which can test thousands of compounds’ effects on diseased cells every day — to search for drug candidates with the potential to affect the abnormal expression of these genes or the stress response of ALS cells. A compound that has an impact on these indicators of ALS could be meaningful for treating the disease, he says.

Prof. Weil is the director of the new Cell Screening Facility for Personalized Medicine at TAU. The facility is dedicated to finding potential drugs for rare and Jewish hereditary diseases.

Finding has implications for alcoholism and other patterns of addictive behavior

Research from the National Institutes of Health has identified neural circuits in mice that are involved in the ability to learn and alter behaviors. The findings help to explain the brain processes that govern choice and the ability to adapt behavior based on the end results.

Researchers think this might provide insight into patterns of compulsive behavior such as alcoholism and other addictions.

“Much remains to be understood about exactly how the brain strikes the balance between learning a behavioral response that is consistently rewarded, versus retaining the flexibility to switch to a new, better response,” said Kenneth R. Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism. “These findings give new insight into the process and how it can go awry.”

The study, published online in Nature Neuroscience, indicates that specific circuits in the forebrain play a critical role in choice and adaptive learning.

Like other addictions, alcoholism is a disease in which voluntary control of behavior progressively diminishes and unwanted actions eventually become compulsive. It is thought that the normal brain processes involved in completing everyday activities become redirected toward finding and abusing alcohol.

The research, conducted by investigators from NIAAA, with support from the National Institute of Mental Health and the University of Cambridge, England, used a variety of approaches to study choice.

Researchers used a simple choice task in which mice viewed images on a computer touchscreen and learned to touch a specific image with their nose to get a food reward. Using various techniques to visualize and record neural activity, researchers found that as the mice learned to consistently make a choice, the brain’s dorsal striatum was activated. The dorsal striatum is thought to play an important role in motivation, decision-making, and reward.

Conversely, when the mice later had to shift to a new choice to receive a reward, the dorsal striatum quieted while regions in the prefrontal cortex, an area involved in decision-making and complex cognitive processes, became active.

Building upon these findings, the authors next deleted or pharmacologically blocked a component of nerve cells which normally binds the neurochemical glutamate (specifically, the GluN2B subunit of the NMDA receptor) within two different areas of the brain, the striatum and the frontal cortex. Previous studies have shown that GluN2B plays a role in memory, spatial reference, and attention. Researchers found that making dorsal striatal GluN2B inactive markedly slowed learning, while shutting down GluN2B in the prefrontal cortex made the mice less able to relearn the touchscreen reward task after the reward image was changed.

“These data add to what we understand about the neural control of behavioral flexibility and striatal learning by identifying GluN2B as a critical molecular substrate to both processes,” said the study’s senior author, Andrew Holmes, Ph.D., Laboratory Chief and Principal Investigator of the NIAAA Laboratory of Behavioral and Genomic Neuroscience.

“This is particularly intriguing for future studies because NMDA receptors are a major target for alcohol and contribute to important features of alcoholism, such as withdrawal. These new findings suggest that GluN2B in corticostriatal circuits may also play a key role in driving the transition from controlled drinking to compulsive abuse that characterizes alcoholism.”

A hallmark of neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s is that by the time symptoms appear, significant brain damage has already occurred—and currently there are no treatments that can reverse it. A team of SRI International researchers has demonstrated that measurements of electrical activity in the brains of mouse models of Huntington’s disease could indicate the presence of disease before the onset of major symptoms. The findings, “Longitudinal Analysis of the Electroencephalogram and Sleep Phenotype in the R6/2 Mouse Model of Huntington’s Disease,” are published in the July 2013 issue of the neurology journal Brain, published by Oxford University Press.

SRI researchers led by Stephen Morairty, Ph.D., a director in the Center for Neuroscience in SRI Biosciences, and Simon Fisher, Ph.D., a postdoctoral fellow at SRI, used electroencephalography (EEG), a noninvasive method commonly used in humans, to measure changes in neuronal electrical activity in a mouse model of Huntington’s disease. Identification of significant changes in the EEG prior to the onset of symptoms would add to evidence that the EEG can be used to identify biomarkers to screen for the presence of a neurodegenerative disease. Further research on such potential biomarkers might one day enable the tracking of disease progression in clinical trials and could facilitate drug development.

“EEG signals are composed of different frequency bands such as delta, theta and gamma, much as light is composed of different frequencies that result in the colors we call red, green and blue,” explained Thomas Kilduff, Ph.D., senior director, Center for Neuroscience, SRI Biosciences. “Our research identified abnormalities in all three of these bands in Huntington’s disease mice. Importantly, the activity in the theta and gamma bands slowed as the disease progressed, indicating that we may be tracking the underlying disease process.”

EEG has shown promise as an indicator of underlying brain dysfunction in neurodegenerative diseases, which otherwise occurs surreptitiously until symptoms appear. Until now, most investigations of EEG in patients with neurodegenerative diseases and in animal models of neurodegenerative diseases have shown significant changes in EEG patterns only after disease symptoms occurred.

“Our breakthrough is that we have found an EEG signature that appears to be a biomarker for the presence of disease in this mouse model of Huntington’s disease that can identify early changes in the brain prior to the onset of behavioral symptoms,” said Morairty, the paper’s senior author. “While the current study focused on Huntington’s disease, many neurodegenerative diseases produce changes in the EEG that are associated with the degenerative process. This is the first step in being able to use the EEG to predict both the presence and progression of neurodegenerative diseases.”

Although previous studies have shown there are distinct and extensive changes in EEG patterns in Alzheimer’s and Huntington’s disease patients, researchers are looking for changes that may occur decades before disease onset.

Huntington’s disease is an inherited disorder that causes certain nerve cells in the brain to die, resulting in motor dysfunction, cognitive decline and psychiatric symptoms. It is the only major neurodegenerative disease where the cause is known with certainty: a genetic mutation that produces a change in a protein that is toxic to neurons.

Latest advances in capturing data on brain activity and eye movement are being combined to open up a host of ‘mindreading’ possibilities for the future. These include the potential development of a system that can detect when drivers are in danger of falling asleep at the wheel.

The research has been undertaken at the University of Leicester with funding from the Engineering and Physical Sciences Research Council (EPSRC), and in collaboration with the University of Buenos Aires in Argentina.

The breakthrough involves bringing two recent developments in the world of technology together: high-speed eye tracking that records eye movements in unprecedented detail using cutting-edge infra-red cameras*; and high-density electroencephalograph** (EEG) technology that measures electrical brain activity with millisecond precision through electrodes placed on the scalp.

The research has overcome previous technological challenges which made it difficult to monitor eye movement and brain activity simultaneously. The team has done this by developing novel signal processing techniques.

This could be the first step towards a system that combines brain and eye monitoring to automatically alert drivers who are showing signs of drowsiness. The system would be built into the vehicle and connected unobtrusively to the driver, with the EEG looking out for brain signals that only occur in the early stages of sleepiness. The eye tracker would reinforce this by looking for erratic gaze patterns symptomatic of someone starting to feel drowsy and different from those characteristic of someone driving who is constantly looking out for hazards. Fatigue has been estimated to account for around 20 per cent of traffic accidents on the UK’s motorways.***

The breakthrough achieved by the University of Leicester could also ultimately be built on to deliver many other everyday applications in the years ahead. For example:

• Computer games of the future could dispense with the need for the player to physically interact with any type of console, mouse or other hand-operated system. Instead, eye movement and brain activity data would be collected and processed to indicate what action the player wants to take. By distinguishing the tiny differences in various types of brain activity, the EEG would identify the precise action the player desires (e.g. run, jump or throw), while the eye movement data would show exactly where on the screen the player was looking when they had this thought. This information could be combined to enable the correct action to occur. An unobtrusive headset would be all that would be required to capture the necessary data.
• People who have no arm functionality could move their wheelchairs simply through their eye movements. These movements could be tracked and the corresponding brain activity analysed to identify when these indicate a desire to move in a certain direction. This would then automatically activate a steering and propulsion mechanism that would drive the wheelchair to that place.
• The breakthrough could also provide the basis for improved tests to diagnose dyslexia and other reading disorders. Current tests revolve around a rapid succession of single words flashed onto a computer screen, with the resulting brain activity monitored by EEG. The new technique could enable the person being tested to move their eyes and read longer passages of text in a natural way, making the tests much more realistic and revealing.
• With the basic concept now demonstrated successfully, the team aim to continue their work and eventually develop software that, in real time, automatically monitors both eye movement and brain activity.
• Dr Matias Ison, who has led the research, says: “Historically, eye-tracking and EEG have evolved as independent fields. We have managed to overcome the challenges that were standing in the way of integrating these technologies. This is already leading to a much better understanding of how the brain responds when the eyes are moving. Monitoring the alertness of drivers is just one of many potential applications for this work. Building on the foundation provided by our EPSRC-funded project, we hope to see the first of these starting to become feasible within the next three to five years.”

A new combination of tissue engineering techniques could reduce the need for nerve grafts, according to new research by The Open University. Regeneration of nerves is challenging when the damaged area is extensive, and surgeons currently have to take a nerve graft from elsewhere in the body, leaving a second site of damage. Nerve grafts contain aligned tissue structures and Schwann cells that support and guide neuron growth through the damaged area, encouraging function to be restored. The research, published in Biomaterials, reported a way to manufacture artificial nerve tissue with the potential to be used as an alternative to nerve grafts.

Pieces of Engineered Neural Tissue (EngNT) are formed by controlling natural Schwann cell behaviour in a three-dimensional collagen gel so that the cells elongate and align, then a stabilisation process removes excess fluid to leave robust artificial tissues. These living biomaterials contain aligned Schwann cells in an aligned collagen environment, recreating key features of normal nerve tissue.

Incorrect orientation of regenerating nerve cells can lead to delays in repair, scarring and poor restoration of nerve function. Much research has taken place into how support cells (Schwann cells) can be combined with materials to guide nerve regeneration. The new technology from The Open University avoids the use of synthetic materials by building neural tissue from collagen, a protein that is abundant in normal nerve tissue. Building the artificial tissue from natural proteins and directing the cellular alignment using normal cell-material interactions means the EngNT can integrate effectively at the repair site.

Dr James Phillips, Lecturer in Health Sciences at The Open University, said: “We previously reported how self-alignment of Schwann cells could be achieved by using a tethered collagen hydrogel, which exploited cells’ natural ability to orientate in the appropriate direction by using their internal contraction forces. Our current research shows that cell-alignment in the hydrogel can be stabilised using plastic compression. The compression removes fluid from the gels, leaving a strong and stable aligned structure that has many features in common with nerve tissue.”

The team incorporated Schwann cells within the aligned material to form artificial neural tissue that could potentially be used in peripheral nerve repair. The technique could be applied to other regenerative medicine scenarios, where a stable artificial tissue containing aligned cellular architecture would be of benefit.