Neuroscience

Innate ability to identify quantities previews future mathematics performance

Babies who are good at telling the difference between large and small groups of items even before learning how to count are more likely to do better with numbers in the future, according to new research from the Duke Institute for Brain Sciences. 

The use of Arabic numerals to represent different values is a characteristic unique to humans, not seen outside our species. But we aren’t born with this skill. Infants don’t have the words to count to 10. So, scientists have hypothesized that the rudimentary sense of numbers in infants is the foundation for higher-level math understanding. 

A new study, appearing online in the Oct. 21 Proceedings of the National Academy of Sciences, suggests that children do, in fact, tap into this innate numerical ability when learning symbolic mathematical systems. The Duke researchers found that the strength of an infant’s inborn number sense can be predictive of the child’s future mathematical abilities.  

"When children are acquiring the symbolic system for representing numbers and learning about math in school, they’re tapping into this primitive number sense," said Elizabeth Brannon, Ph.D., a professor of psychology and neuroscience, who led the study. "It’s the conceptual building block upon which mathematical ability is built."

Brannon explained that babies come into the world with a rudimentary understanding referred to as a primitive number sense. When looking at two collections of objects, primitive number sense allows them to identify which set is numerically larger even without verbal counting or using Arabic numerals. For example, a person instinctively knows a group of 15 strawberries is more than six oranges, just by glancing. 

Understanding how infants and young children conceptualize and understand number can lead to the development of new mathematics education strategies, said Brannon’s colleague, Duke psychology and neuroscience graduate student Ariel Starr. In particular, this knowledge can be used to design interventions for young children who have trouble learning mathematics symbols and basic methodologies.

To test for primitive number sense, Brannon and Starr analyzed 48 6-month-old infants to see whether they could recognize numerical changes, capitalizing on the interest most babies show in things that change. They placed each baby in front of two screens, one that always showed the same number of dots (e.g., eight), changing in size and position, and another that switched between two different numerical values (e.g., eight and 16 dots). All the arrays of dots changed frequently in size and position. In this task, babies that could tell the difference between the two numerical values (e.g., eight and 16) looked longer at the numerically changing screen.  

Brannon and Starr then tested the same children at 3.5 years of age with a non-symbolic number comparison game. The children were shown two different arrays and asked to choose which one had more dots without counting them. In addition, the children took a standardized math test scaled for pre-schoolers, as well as a standardized IQ test. Finally, the researchers gave the children a simple verbal task to identify the largest number word each child could concretely understand.

"We found that infants with higher preference scores for looking at the numerically changing screen had better primitive number sense three years later compared to those infants with lower scores," Starr said. "Likewise, children with higher scores in infancy performed better on standardized math tests."

Brannon said the findings point to a real connection between symbolic math and quantitative abilities that are present in infancy before education takes hold and shapes our mathematical abilities.

"Our study shows that infant number sense is a predictor of symbolic math," Brannon said. "We believe that when children learn the meaning of number words and symbols, they’re likely mapping those meanings onto pre-verbal representations of number that they already have in infancy," she said. 

"We can’t measure a baby’s number sense ability at 6 months and know how they’ll do on their SATs," Brannon added. "In fact our infant task only explains a small percentage of the variance in young children"s math performance. But our findings suggest that there is cognitive overlap between primitive number sense and symbolic math. These are fundamental building blocks."

Buck Institute study provides insight for new therapeutics that target the interaction between ApoE4 and a Sirtuin protein

The major genetic risk factor for Alzheimer’s disease (AD), present in about two-thirds of people who develop the disease, is ApoE4, the cholesterol-carrying protein that about a quarter of us are born with. But one of the unsolved mysteries of AD is how ApoE4 causes the risk for the incurable, neurodegenerative disease. In research published this week in The Proceedings of the National Academy of Sciences, researchers at the Buck Institute found a link between ApoE4 and SirT1, an “anti-aging protein” that is targeted by resveratrol, present in red wine.

The Buck researchers found that ApoE4 causes a dramatic reduction in SirT1, which is one of seven human Sirtuins. Lead scientists Rammohan Rao, PhD, and Dale Bredesen, MD, founding CEO of the Buck Institute, say the reduction was found both in cultured neural cells and in brain samples from patients with ApoE4 and AD. “The biochemical mechanisms that link ApoE4 to Alzheimer’s disease have been something of a black box. However, recent work from a number of labs, including our own, has begun to open the box,” said Bredesen.

The Buck group also found that the abnormalities associated with ApoE4 and AD, such as the creation of phospho-tau and amyloid-beta, could be prevented by increasing SirT1. They have identified drug candidates that exert the same effect. “This research offers a new type of screen for Alzheimer’s prevention and treatment,” said Rammohan V. Rao, PhD, co-author of the study, and an Associate Research Professor at the Buck. “One of our goals is to identify a safe, non-toxic treatment that could be given to anyone who carries the ApoE4 gene to prevent the development of AD.”

In particular, the researchers discovered that the reduction in SirT1 was associated with a change in the way the amyloid precursor protein (APP) is processed. Rao said that ApoE4 favored the formation of the amyloid-beta peptide that is associated with the sticky plaques that are one of the hallmarks of the disease. He said with ApoE3 (which confers no increased risk of AD), there was a higher ratio of the anti-Alzheimer’s peptide, sAPP alpha, produced, in comparison to the pro-Alzheimer’s amyloid-beta peptide. This finding fits very well with the reduction in SirT1, since overexpressing SirT1 has previously been shown to increase ADAM10, the protease that cleaves APP to produce sAPP alpha and prevent amyloid-beta.

AD affects over 5 million Americans – there are no treatments that are known to cure, or even halt the progression of symptoms that include loss of memory and language. Preventive treatments are particularly needed for the 2.5% of the population that carry two genes for ApoE4, which puts them at an approximate 10-fold higher risk of developing AD, as well as for the 25% of the population with a single copy of the gene. The group hopes that the current work will identify simple, safe therapeutics that can be given to ApoE4 carriers to prevent the development of Alzheimer’s disease.

Poor sleep quality may impact Alzheimer’s disease onset and progression. This is according to a new study led by researchers at the Johns Hopkins Bloomberg School of Public Health who examined the association between sleep variables and a biomarker for Alzheimer’s disease in older adults. The researchers found that reports of shorter sleep duration and poorer sleep quality were associated with a greater β-Amyloid burden, a hallmark of the disease. The results are featured online in the October issue of JAMA Neurology.

“Our study found that among older adults, reports of shorter sleep duration and poorer sleep quality were associated with higher levels of β-Amyloid measured by PET scans of the brain,” said Adam Spira, PhD, lead author of the study and an assistant professor with the Bloomberg School’s Department of Mental Health. “These results could have significant public health implications as Alzheimer’s disease is the most common cause of dementia, and approximately half of older adults have insomnia symptoms.”

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. According to the National Institutes of Health, as many as 5.1 million Americans may have the disease, with first symptoms appearing after age 60. Previous studies have linked disturbed sleep to cognitive impairment in older people.

In a cross-sectional study of adults from the neuro-imagining sub-study of the Baltimore Longitudinal Study of Aging with an average age of 76, the researchers examined the association between self-reported sleep variables and β-Amyloid deposition. Study participants reported sleep that ranged from more than seven hours to no more than five hours. β-Amyloid deposition was measured by the Pittsburgh compound B tracer and PET (positron emission tomography) scans of the brain. Reports of shorter sleep duration and lower sleep quality were both associated with greater Αβ buildup.

“These findings are important in part because sleep disturbances can be treated in older people. To the degree that poor sleep promotes the development of Alzheimer’s disease, treatments for poor sleep or efforts to maintain healthy sleep patterns may help prevent or slow the progression of Alzheimer disease,” said Spira.  He added that the findings cannot demonstrate a causal link between poor sleep and Alzheimer’s disease, and that longitudinal studies with objective sleep measures are needed to further examine whether poor sleep contributes to or accelerates Alzheimer’s disease.

In a biological quirk that promises to provide researchers with a new approach for studying and potentially treating Fragile X syndrome, scientists at the University of Massachusetts Medical School (UMMS) have shown that knocking out a gene important for messenger RNA (mRNA) translation in neurons restores memory deficits and reduces behavioral symptoms in a mouse model of a prevalent human neurological disease. These results, published today in Nature Medicine, suggest that the prime cause of the Fragile X syndrome may be a translational imbalance that results in elevated protein production in the brain. Restoration of this balance may be necessary for normal neurological function.

"Biology works in strange ways," said Joel Richter, PhD, professor of molecular medicine at UMMS and senior author on the study. "We corrected one genetic mutation with another, which in effect showed that two wrongs make a right. Mutations in each gene result in impaired brain function, but in our studies, we found that mutations in both genes result in normal brain function. This sounds counter-intuitive, but in this case that seems to be what has happened."

Fragile X syndrome, the most common form of inherited mental retardation and the most frequent single-gene cause of autism, is a genetic condition resulting from a CGG repeat expansion in the DNA sequence of the Fragile X (Fmr1) gene required for normal neurological development. People with Fragile X suffer from intellectual disability as well as behavioral and learning challenges. Depending on the length of the CGG repeat, intellectual disabilities can range from mild to severe.

While scientists have identified the genetic mutation that causes Fragile X, on a molecular level they still don’t know much about how the disease works or what precisely goes wrong in the brain as a result. What is known is that the Fmr1 gene codes for the Fragile X protein (FMRP). This protein probably has several functions throughout the neuron but its main activity is to repress the translation of as many as 1,000 different mRNAs. By doing this, FMRP controls synaptic plasticity and higher brain function. Mice without the Fragile X gene, for instance, have a 15 to 20 percent overall elevation in neural protein production. It is thought that the inability to repress mRNA translation and the resulting increase in neural proteins may somehow hamper normal synaptic function in patients with Fragile X. But because FMRP binds so many mRNAs, and some proteins become more elevated than others, parsing which mRNA or combination of mRNAs is responsible for Fragile X pathology is a daunting task.

From Frog Egg to Fragile X

For years, Dr. Richter had been studying how translation, the process in which cellular ribosomes create proteins, went from dormant to active in frog eggs. He discovered the key gene controlling this process, the RNA binding protein CPEB. In 1998, Richter found the CPEB protein in the rodent brain where it played an important role in regulating how synapses talk to each other. At this point, his work began to move from exploring the role of CPEB in the developmental biology of the frog to how the CPEB protein impacted learning and memory. A serendipitous research symposium with colleagues at Cold Spring Harbor got him thinking about CPEB and Fragile X syndrome.

"Here I was, an outsider, a molecular biologist who had worked for years with frog eggs, in the same room with neurobiologists and neurologists, when they started talking about Fragile X syndrome and translational activity," said Richter. "It got me thinking that the CPEB protein might be a path to restoring the translational imbalance they were discussing."

Richter knew that CPEB stimulated translation and that FMRP repressed it. He also knew that animal models lacking the CPEB protein had memory deficits and that both proteins bound to many of the same mRNAs – the overlap may be as higher as 33 percent. The thought was that by taking away a protein that stimulated translation might counterbalance the loss of the repressor FMRP protein, thereby restoring translational homeostasis in the brain and normal neurological function.

"It was one of those kind of goofy ‘what if’ sort of things," said Richter.

To test his hypothesis, Richter developed a double knockout mouse model that lacked both the FMRP gene that caused Fragile X and the CPEB gene. When they began measuring for Fragile X pathologies what they found was almost too good to be true.

"We measured a host of factors, biochemical, morphological, electrophysiological and behavioral phenotypes," said Richter. "And we kept finding the same thing. By knocking out both the FMRP and CPEB genes we were able to restore levels of protein synthesis to normal and corrected the disease characteristics of the Fragile X mice, making them almost indistinguishable from wild type mice."

Most importantly, tests to evaluate short-term memory in the double knockout mice also showed normal results with no indications of Fragile X pathology. This suggested an experiment to test whether CPEB might be a potential therapeutic target for Fragile X to benefit patients. Richter and colleagues took adult Fragile X mice and injected a lentivirus that expresses a small RNA to knock down CPEB in the hippocampus, which is a brain region that is important for short-term memory. Subsequent tests showed improved short-term memory in these mice, indicating that at least this one characteristic of Fragile X syndrome, which is generally thought to be a developmental disorder, can be reversed in adults.

"People with Fragile X make too much protein," said Richter. "By using CPEB to recalibrate the cellular machinery that makes protein we’ve shown that tamping down this process has a profoundly good impact on mouse models with Fragile X. It may be that a similar approach could be beneficial for kids with this disease."

The next step for Richter and colleagues is to determine which, of the more than 300 mRNAs that both CPEB and FMRP bind to, contribute to Fragile X syndrome and how. They’ll also begin looking at small molecules and other avenues that, like the ablation of the CPEB protein, might be able to slow down the synthesis of protein. “There are several small molecules that we know affect the translational apparatus,” Richter said. “Some cross the blood/brain barrier, some are toxic, and some are not. We’d like to investigate those.”

"This is another, great example of how basic science translates to human disease," said Richter. "If we had started out looking at the human brain, not knowing about the CPEB protein and its role in translational activity, we wouldn’t have had any idea where to start or what to look for. But because we started out in the frog, where things are much easier to see, and because more often than not these processes are conserved, we’ve learned something new and totally unexpected that may have a profound impact on human disease."

Many negative effects of drinking, such as transitioning into heavy alcohol use, often take place during adolescence and can contribute to long-term negative health outcomes as well as the development of alcohol use disorders. A new study of adolescent drinking and its genetic and environmental influences has found that different trajectories of adolescent drinking are preceded by discernible gene-parenting interactions, specifically, the mu-opioid receptor (OPRM1) genotype and parental-rule-setting.

Results will be published in the March 2014 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"Heavy drinking in adolescence can lead to alcohol-related problems and alcohol dependence later in life," said Carmen Van der Zwaluw, an assistant professor at Radboud University Nijmegen as well as corresponding author for the study. "It has been estimated that 40 percent of adult alcoholics were already heavy drinkers during adolescence. Thus, tackling heavy drinking in adolescence may prevent later alcohol-related problems."

Van der Zwaluw said that both the dopamine receptor D2 (DRD2) and OPRM1 genes are known to play a large role in the neuro-reward mechanisms associated with the feelings of pleasure that result from drinking, as well as from eating, having sex, and the use of other drugs.

"Different genotypes may result in different neural responses to alcohol or different motivations to drink," she said. "For example, OPRM1 G-allele carriers have been shown to experience more positive feelings after drinking, and to drink more often to enhance their mood than people with the OPRM1 AA genotype. In addition, we chose to examine the influence of parental alcohol-specific rules because research has shown that, more than general measures of parental monitoring, alcohol-specific rule-setting has a considerable and consistent effect on adolescents’ drinking behavior."

Van der Zwaluw and her colleagues used data from the Dutch Family and Health study that consisted of six yearly waves, beginning in 2002 and including only adolescents born in the Netherlands. The final sample of 596 adolescents (50% boys) were on average 14.3 years old at Time 1 (T1), 15.3 at T2, 16.3 at T3, 17.7 at T4, 18.7 years at T5, and 19.7 years at T6. Saliva samples were collected in the fourth wave to enable genetic testing. Participants were subsequently divided into three distinct groups of adolescent drinkers; light drinkers (n=346), moderate drinkers (n=178), and heavy drinkers (n=72).

"It was found that adolescent drinkers could be discriminated into three groups: light, moderate, and heavy drinkers," said Van der Zwaluw. "Comparisons between these three groups showed that light drinkers were more often carriers of the OPRM1 AA ‘non-risk’ genotype, and reported stricter parental rules than moderate drinkers. In the heavy drinking group, the G-allele carriers, but not those with the AA-genotype, were largely affected by parental rules: more rules resulted in lower levels of alcohol use."

Van der Zwaluw explained that although evidence for the genetic liability of heavy alcohol use has been shown repeatedly, debate continues over which genes are responsible for this liability, what the causal mechanisms are, and whether and how it interacts with environmental factors. “Longitudinal studies examining the development of alcohol use over time, in a stage of life that often precedes serious alcohol-related problems, can shed more light on these issues,” she said. “This paper confirms important findings of others; showing an association of the OPRM1 G-allele with adolescent alcohol use and an effect of parental rule-setting. Additionally, it adds to the literature by demonstrating that, depending on genotype, adolescents are differently affected by parental rules.”

The bottom line is that parents can be a positive influence, Van der Zwaluw noted. “This study shows that strict parental rules prevent youth from drinking more alcohol,” she said. “However, one should keep in mind that every adolescent responds differently to parenting efforts, and that the effects of parenting may depend on the genetic make-up of the adolescent.”

Features like the wrinkles on your forehead and the way you move may reflect your overall health and risk of dying, according to recent health research. But do physicians consider such details when assessing patients’ overall health and functioning?

In a survey of approximately 1,200 Taiwanese participants, Princeton University researchers found that interviewers — who were not health professionals but were trained to administer the survey — provided health assessments that were related to a survey participant’s risk of dying, in part because they were attuned to facial expressions, responsiveness and overall agility.

The researchers report in the journal Epidemiology that these assessments were even more accurate predictors of dying than assessments made by physicians or even the individuals themselves. The findings show that survey interviewers, who typically spend a fair amount of time observing participants, can glean important information regarding participants’ health through thorough observations.  

"Your face and body reveal a lot about your life. We speculate that a lot of information about a person’s health is reflected in their face, movements, speech and functioning, as well as in the information explicitly collected during interviews," said Noreen Goldman, Hughes-Rogers Professor of Demography and Public Affairs in the Woodrow Wilson School.

Together with lead author of the paper and Princeton Ph.D. candidate Megan Todd, Goldman analyzed data collected by the Social Environment and Biomarkers of Aging Study (SEBAS). This study was designed by Goldman and co-investigator Maxine Weinstein at Georgetown University to evaluate the linkages among the social environment, stress and health. Beginning in 2000, SEBAS conducted extensive home interviews, collected biological specimens and administered medical examinations with middle-aged and older adults in Taiwan. Goldman and Todd used the 2006 wave of this study, which included both interviewer and physician assessments, for their analysis. They also included death registration data through 2011 to ascertain the survival status of those interviewed.  

The survey used in the study included detailed questions regarding participants’ health conditions and social environment. Participants’ physical functioning was evaluated through tasks that determined, for example, their walking speed and grip strength. Health assessments were elicited from participants, interviewers and physicians on identical five-point scales by asking “Regarding your/the respondent’s current state of health, do you feel it is excellent (5), good (4), average (3), not so good (2) or poor (1)?”

Participants answered this question near the beginning of the interview, before other health questions were asked. Interviewers assessed the participants’ health at the end of the survey, after administering the questionnaire and evaluating participants’ performance on a set of tasks, such as walking a short distance and getting up and down from a chair. And physicians — who were hired by the study and were not the participants’ primary care physicians — provided their assessments after physical exams and reviews of the participants’ medical histories. (Study investigators did not provide special guidance about how to rate overall health to any group.)

In order to understand the many variables that go into predicting mortality, Goldman and Todd factored into their statistical models such socio-demographic variables as sex, place of residence, education, marital status, and participation in social activities. They also considered chronic conditions, psychological wellbeing (such as depressive symptoms) and physical functioning to account for a fuller picture of health.

"Mortality is easy to measure because we have death records indicating when a person has died," Goldman said. "Overall health, on the other hand, is very complicated to measure but obviously very important for addressing health policy issues."

Two unexpected results emerged from Goldman and Todd’s analysis. The first: physicians’ ratings proved to be weak predictors of survival. “The physicians performed a medical exam equivalent to an annual physical exam, plus an abdominal ultrasound; they have specialized knowledge regarding health conditions,” Goldman explained. “Given access to such information, we anticipated stronger, more accurate predictions of death,” she said. “These results call into question previous studies’ assumptions that physicians’ ‘objective health’ ratings are superior to ‘subjective’ ratings provided by the survey participants themselves.”

In a second surprising finding, the team found that interviewers’ ratings were considerably more powerful for predicting mortality than self-ratings. This is likely, Goldman said, because interviewers considered respondents’ movements, appearance and responsiveness in addition to the detailed health information gathered during the interviews. Also, Goldman posits, interviewer ratings are probably less affected by bias than self-reports. 

"The ‘self-rated health’ question is religiously used by health researchers and social scientists, and, although it has been shown to predict mortality, it suffers from many biases. People use it because it’s easy and simple,” Goldman continued. "But the problem with self-rated health is that we have no idea what reference group the respondent is using when evaluating his or her own health. Different ethnic and racial groups respond differently as do varying socioeconomic groups. We need other simple ways to rate individual health instead of relying so heavily on self-rated health."

One way, Goldman suggests, is by including interviewer ratings in surveys along with self-ratings: “This is a straightforward and cost-free addition to a questionnaire that is likely to improve our measurement of health in any population,” Goldman said.

Teaching two-legged robots a stable, robust “human” way of walking – this is the goal of the international research project “KoroiBot” with scientists from seven institutions from Germany, France, Israel, Italy and the Netherlands. The experts from the areas of robotics, mathematics and cognitive sciences want to study human locomotion as exactly as possible and transfer this onto technical equipment with the assistance of new mathematical processes and algorithms. The European Union is financing the three-year research project that started in October 2013 with approx. EUR 4.16 million. The scientific coordinator is Prof. Dr. Katja Mombaur from Heidelberg University.

Whether as rescuers in disaster areas, household helps or as “colleagues” in modern work environments: there are numerous possible areas of deployment for humanoid robots in the future. “One of the major challenges on the way is to enable robots to move on two legs in different situations, without an accident – in spite of unknown terrain and also with possible disturbances,” explains Prof. Mombaur, who heads the working group “Optimisation in Robotics and Biomechanics” at Heidelberg University’s Interdisciplinary Center for Scientific Computing (IWR).

In the KoroiBot project the researchers will study the way humans walk e.g. on stairs and slopes, on soft and slippery ground or over beams and seesaws, and create mathematical models. Besides developing new optimisation and learning processes for walking on two legs, they aim to implement this in practice with existing robots. In addition, the research results are to flow into planning new design principles for the next generation of robots.

Besides Prof. Mombaur’s group, the working group “Simulation and Optimisation” is also involved in the project at the IWR. The Heidelberg scientists will investigate the way movement of humans and robots can be turned into mathematical models. Furthermore, the teams want to create optimised walking movements for different demands and develop new model-based control algorithms. Just under EUR 900,000 of the European Union funding is being channelled to Heidelberg.

Partners in the international consortium are, besides Heidelberg University, leading institutions in the field of robotics. These include the Karlsruhe Institute of Technology (KIT), the Centre National de la Recherche Scientifique (CNRS) with three laboratories, the Istituto Italiano di Tecnologia (IIT) and the Delft University of Technology in the Netherlands. Experts from the University of Tübingen and the Weizmann Institute of Science in Israel will contribute from the angle of cognitive sciences.

Besides the targeted use of robotics, the scientists expect possible applications in medicine, e.g. for controlling intelligent artificial limbs. They see further areas of application in designing and regulating exoskeletons as well as in computer animation and in game design.

Joint research from the University of Alabama at Birmingham Department of Psychology and Auburn University indicates that brain scans show signs of autism that could eventually support behavior-based diagnosis of autism and effective early intervention therapies. The findings appear online today in Frontiers in Human Neuroscience as part of a special issue on brain connectivity in autism.

“This research suggests brain connectivity as a neural signature of autism and may eventually support clinical testing for autism,” said Rajesh Kana, Ph.D., associate professor of psychology and the project’s senior researcher. “We found the information transfer between brain areas, causal influence of one brain area on another, to be weaker in autism.”

The investigators found that brain connectivity data from 19 paths in brain scans predicted whether the participants had autism, with an accuracy rate of 95.9 percent.

Kana, working with a team including Gopikrishna Deshpande, Ph.D., from Auburn University’s MRI Research Center, studied 15 high-functioning adolescents and adults with autism, as well as 15 typically developing control participants ages 16-34 years. Kana’s team collected all data in his autism lab at UAB that was then analyzed using a novel connectivity method at Auburn.

The current study showed that adults with autism spectrum disorders processed social cues differently than typical controls. It also revealed the disrupted brain connectivity that explains their difficulty in understanding social processes.

“We can see that there are consistently weaker brain regions due to the disrupted brain connectivity,” Kana said. “There’s a very clear difference.”

Participants in this study were asked to choose the most logical of three possible endings as they watched a series of comic strip vignettes while a functional MRI scanner measured brain activity.

The scenes included a glass about to fall off a table and a man enjoying the music of a street violinist and giving him a cash tip. Most participants in the autism group had difficulty in finding a logical end to the violinist scenario, which required an understanding of emotional and mental states. The current study showed that adults with autism spectrum disorders struggle to process subtle social cues, and altered brain connectivity may underlie their difficulty in understanding social processes.

“We can see that the weaker connectivity hinders the cross-talk among brain regions in autism,” Kana said.

Kana plans to continue his research on autism.

“Over the next five to 10 years, our research is going in the direction of finding objective ways to supplement the diagnosis of autism with medical testing and testing the effectiveness of intervention in improving brain connectivity,” Kana said.

Autism is currently diagnosed through interviews and behavioral observation. Although autism can be diagnosed by 18 months, in reality, earliest diagnoses occur around ages 4-6 as children face challenges in school or social settings.

“Parents usually have a longer road before getting a firm diagnosis for their child now,” Kana said. “You lose a lot of intervention time, which is so critical. Brain imaging may not be able to replace the current diagnostic measures; but if it can supplement them at an earlier age, that’s going to be really helpful.”

Video-based teaching helps teens with autism learn important social skills, and the method eventually could be used widely by schools with limited resources, a Michigan State University researcher says.

The diagnosis rate for Autism Spectrum Disorder for 14- to 17-year-olds has more than doubled in the past five years, according to the Centers for Disease Control and Prevention. Yet previous research has found very few strategies for helping adolescents with autism develop skills needed to be successful, especially in group settings.

“Teaching social skills to adolescents with ASD has to be effective and practical,” said Joshua Plavnick, assistant professor of special education at MSU. “Using video-based group instruction regularly could promote far-reaching gains for students with ASD across many social behaviors.”

Plavnick developed group video teaching techniques with colleagues while a postdoctoral fellow at the University of North Carolina’s Frank Porter Graham Child Development Institute. Their findings are published in the research journal Exceptional Children.

Previous studies have shown many people with autism are more likely to pay attention when an innovative technology delivers information. Before Plavnick’s work, however, there were no investigations of video modeling as an option for teaching social skills to more than one adolescent with ASD at the same time.

The team recruited 13- to 17-year-old students with ASD and used laptops or iPads to offer group video instruction on social behaviors, such as inviting a peer to join an activity. One facilitator showed four students video footage of people helping one another clean up a mess, for example, and then gave them opportunities to practice the same skills in the classroom.

According to the researchers, the students demonstrated a rapid increase in the level of complex social behaviors each time video-based group instruction was used. Students sustained those social behaviors at high levels, even when the videos were used less often.

The students’ parents also completed anonymous surveys and indicated high levels of satisfaction. One reported their child started asking family members to play games together, a skill the teen had never before displayed at home.

Most schools do not have appropriate staff resources to provide one-on-one help for students with autism. The video can be used with a small group all at once and has been shown to be effective.

“Video-based group instruction is important, given the often limited resources in schools that also face increasing numbers of students being diagnosed with ASD,” said Plavnick, who also has begun implementing the strategy as part of a daily high school-based program.

NIH-funded study suggests sleep clears brain of molecules associated with neurodegeneration

A good night’s rest may literally clear the mind. Using mice, researchers showed for the first time that the space between brain cells may increase during sleep, allowing the brain to flush out toxins that build up during waking hours. These results suggest a new role for sleep in health and disease. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH.

“Sleep changes the cellular structure of the brain. It appears to be a completely different state,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center in New York, and a leader of the study.

For centuries, scientists and philosophers have wondered why people sleep and how it affects the brain. Only recently have scientists shown that sleep is important for storing memories. In this study, Dr. Nedergaard and her colleagues unexpectedly found that sleep may be also be the period when the brain cleanses itself of toxic molecules.

Their results, published in Science, show that during sleep a “plumbing” system, called the glymphatic system, may open, letting fluid flow rapidly through brain. Dr. Nedergaard’s lab recently discovered the glymphatic system helps control whether cerebrospinal fluid (CSF), a clear liquid surrounding the brain and spinal cord, flows through the brain.

“It’s as if Dr. Nedergaard and her colleagues have uncovered a network of hidden caves and  these exciting results highlight the potential importance of the network in normal brain function,” said Roderick Corriveau, Ph.D., a program director at NINDS.

Initially the researchers studied the system by injecting dye into the CSF of mice and watching it flow through their brains while simultaneously monitoring electrical brain activity. The dye flowed rapidly when the mice were unconscious, either asleep or anesthetized.  In contrast, the dye barely flowed when the same mice were awake.

“We were surprised by how little flow there was into the brain when the mice were awake,” said Dr. Nedergaard. “It suggested that the space between brain cells changed greatly between conscious and unconscious states.”

To test this idea, the researchers inserted electrodes into the brain to directly measure the space between brain cells. They found that the space inside the brains increased by 60 percent when the mice were asleep or anesthetized. 

“These are some dramatic changes in extracellular space,” said Charles Nicholson, Ph.D., a professor at New York University’s Langone Medical Center and an expert in measuring the dynamics of brain fluid flow and how it influences nerve cell communication.

Certain brain cells, called glia, control flow through the glymphatic system by shrinking or swelling. Noradrenaline is an arousing hormone that is also known to control cell volume. Treating awake mice with drugs that block noradrenaline induced sleep and increased brain fluid flow and the space between cells, further supporting the link between the glymphatic system and sleep.

Previous studies suggest that toxic molecules involved in neurodegenerative disorders accumulate in the space between brain cells. In this study, the researchers tested whether the glymphatic system controls this by injecting mice with radiolabeled beta-amyloid, a protein associated with Alzheimer’s disease, and measuring how long it lasted in their brains when they were asleep or awake. Beta-amyloid disappeared faster in mice brains when the mice were asleep, suggesting sleep normally clears toxic molecules from the brain.

“These results may have broad implications for multiple neurological disorders,” said Jim Koenig, Ph.D., a program director at NINDS. “This means the cells regulating the glymphatic system may be new targets for treating a range of disorders.”

The results may also highlight the importance of sleep.

“We need sleep.  It cleans up the brain,” said Dr. Nedergaard.

Johns Hopkins scientists have developed new drugs that — at least in a laboratory dish — appear to halt the brain-destroying impact of a genetic mutation at work in some forms of two incurable diseases, amyotrophic lateral sclerosis (ALS) and dementia.

They made the finding by using neurons they created from stem cells known as induced pluripotent stem cells (iPS cells), which are derived from the skin of people with ALS who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.

“Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials,” says Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the research described online in the journal Neuron. “But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It’s individualized brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology.”

Scientists in 2011 discovered that more than 40 percent of patients with an inherited form of ALS and at least 10 percent of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene. The mutation also occurs very often in people with frontotemporal dementia, the second-most-common form of dementia after Alzheimer’s disease. The same research appeared to explain why some people develop both ALS and the dementia simultaneously and that, in some families, one sibling might develop ALS while another might develop dementia.

In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times. Rothstein, who is also director of the Johns Hopkins Brain Science Institute and the Robert Packard Center for ALS Research, used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the “repeats” were causing the brain cell death characteristic of ALS.

In a series of experiments, Rothstein says, they discovered that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted. Normally, RNA-binding proteins facilitate the production of RNA. Instead, in the iPS neurons with the C9ORF72 mutation, the RNA made from the repeating GGGGCC strings was bunching up, gumming up the works by acting like flypaper and grabbing hold of the extremely important RNA binding proteins, including one known as ADARB2,  needed for the proper production of many other cellular RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.

To counter this effect, the researchers developed a number of chemical compounds targeting the problem. This compound behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.

Rothstein says Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing it in human ALS patients with the C9ORF72 mutation in the next several years. In collaboration with the National Institutes of Health, plans are already underway to begin to identify a group of patients with the C9ORF72 mutation for future research.

Rita Sattler, Ph.D., an assistant professor of neurology at Johns Hopkins and the co-investigator of the study, says without iPS technology, the team would have had a difficult time studying the C9ORF72 mutation. “Typically, researchers engineer rodents with mutations that mimic the human glitches they are trying to research and then study them,” she says. “But the nature of the multiple repeats made that nearly impossible.” The iPS cells did the job just as well or even better than an animal model, Sattler says, in part because the experiments could be done using human cells.

“An iPS cell line can be used effectively and rapidly to understand disease mechanisms and as a tool for therapy development,” Rothstein adds. “Now we need to see if our findings translate into a valuable treatment for humans.”

The researchers also analyzed brain tissue from people with the C9ORF72 mutation who died of ALS. They saw evidence of this bunching up and found that the many genes that were altered as a consequence of this mutation in the iPS cells were also abnormal in the brain tissue, thereby showing that iPS cells can be a faithful tool to study the human disease and discover effective therapies.

In the future, the scientists will look at cerebral spinal fluid from ALS patients with the C9ORF72 mutation, searching for proteins that were found both in the fluid and the iPS cells. These may pave the way to develop markers that can be studied by clinicians to see if the treatment is working once the drug therapy is moved to clinical trials.

ALS, sometimes known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, destroys nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary. There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival, Rothstein notes.

Research in mouse whiskers reveals signal pathway from touch neuron to brain

Human fingertips have several types of sensory neurons that are responsible for relaying touch signals to the central nervous system. Scientists have long believed these neurons followed a linear path to the brain with a “labeled-lines” structure. 

But new research on mouse whiskers from Duke University reveals a surprise — at the fine scale, the sensory system’s wiring diagram doesn’t have a set pattern. And it’s probably the case that no two people’s touch sensory systems are wired exactly the same at the detailed level, according to Fan Wang, Ph.D., an associate professor of neurobiology in the Duke Medical School.

The results, which appear online in Cell Reports, highlight a “one-to-many, many-to-one” nerve connectivity strategy. Single neurons send signals to multiple potential secondary neurons, just as signals from many neurons can converge onto a secondary neuron. Many such connections are likely formed by chance, Wang said. This connectivity scheme allows the touch system to have many possible combinations to encode a large repertoire of textures and forms.

"We take our sense of touch for granted," Wang said. "When you speak, you are not aware of the constant tactile feedback from your tongue and teeth. Without such feedback, you won’t be able to say the words correctly. When you write with a pen, you’re mostly unaware of the sensors telling you how to move it."

It’s not feasible to visualize the touch pathways in the human brain at high resolutions. So, Wang and her collaborators from the University of Tsukuba in Japan and the Friedrich Miescher Institute for Biomedical Research in Switzerland used the whiskers of laboratory mice to map how distinct sensor neurons, presumably detecting different mechanical stimuli, are connected to signal the brain. When the sensory neurons are activated, they send the signal along an axon — a long, slender nerve fiber than conducts electric impulses to the brain. The researchers traced signals running the long path from the mouse’s whiskers to the brain.

Wang’s group used a combination of genetic engineering and fluorescent tags delivered by viruses to color-code four different kinds of neurons and map their connections.  

Earlier work by Wang and others had found that all of the 100 to 200 sensors associated with a single whisker project their axons to a large structure representing that whisker in the brain. Each whisker has its own neural representation structure. 

"People have thought that within the large whisker-representing structure, there will be finer-scale, labeled lines," Wang said. "In other words, different touch sensors would send information through separate parallel pathways, into that large structure. But surprisingly, we did not find such organized pathways. Instead, we found a completely unorganized mosaic pattern of connections within the large structure. Information from different sensors is intermixed already at the first relay station inside the brain."

Wang said the next step will be to stimulate the labeled circuits in different ways to see how impulses travel the network.  

"We want to figure out the exact functions and signals transmitted by different sensors during natural tactile behaviors and determine their exact roles on the perception of textures," she said.

Anyone who has suffered through sleepless nights due to uncontrollable itching knows that not all itching is the same. New research at Washington University School of Medicine in St. Louis explains why.

Working in mice, the scientists have shown that chronic itching, which can occur in many medical conditions, from eczema and psoriasis to kidney failure and liver disease, is different from the fleeting urge to scratch a mosquito bite.

That’s because chronic itching appears to incorporate more than just the nerve cells, or neurons, that normally transmit itch signals. The researchers found that in chronic itching, neurons that send itch signals also co-opt pain neurons to intensify the itch sensation.

The new discovery may lead to more effective treatments for chronic itching that target activity in neurons involved in both pain and itch. The research is reported online Oct. 15 in The Journal of Clinical Investigation and will appear in the November print issue.

“In normal itching, there’s a fixed pathway that transmits the itch signal,” said senior investigator Zhou-Feng Chen, PhD, who directs Washington University’s Center for the Study of Itch. “But with chronic itching, many neurons can be turned into itch neurons, including those that typically transmit pain signals. That helps explain why chronic itching can be so excruciating.”

Chen, a professor of anesthesiology, and his colleagues generated mice in which a protein called BRAF always is active and continually sends signals inside itch neurons. The BRAF gene and the protein it makes are involved in the body’s pain response, but scientists didn’t know whether the gene also played a role in itch.

“We thought the animals might be prone to feeling pain rather than itching,” Chen explained. “To our great surprise, the mice scratched spontaneously. At first, we didn’t know why they were scratching, but it turns out we developed a mouse model of chronic itch.”

Further studies discovered that the BRAF protein could turn on many itch genes, and they showed similar changes of gene expression in mice with chronic itch induced by dry skin and in mice with allergic contact dermatitis, two of the skin conditions that frequently cause people to scratch incessantly.

The findings suggest that targeting proteins in the BRAF pathway may open new avenues for treating chronic itch, a condition in which few therapies are effective. One possibility includes using drugs that are prescribed to treat pain.

“Certain drugs are used to inhibit some of the same targets in patients with chronic pain, and those medications also may quiet down itch,” Chen said.

In earlier studies, Chen identified gastrin-releasing peptide (GRP), a substance that carries itch signals to a gene called GRPR (gastrin-releasing peptide receptor) in the spinal cord. In the new study, GRP and GRPR activity was doubled in the genetically altered mice, which could account for some of the increase in the intensity of itching. But other genes that normally are activated by pain also were turned on in the itch pathway, further intensifying the itch sensation.

Surprisingly, however, the mice had a normal response to pain, indicating that the pain and itch pathways are very different.

Unlike scratching a mosquito bite, which usually is only a temporary sensation, chronic itch can persist much longer, according to Chen, also a professor of psychiatry and of developmental biology. His team found that the mice in this study not only scratched spontaneously but also had more severe responses when exposed to substances that normally would induce acute itching.

“In people, chronic itching can last for weeks, months or even years,” Chen said. “These mice are helping us to understand the pathways that can be involved in transmitting itch signals and the many contributors to chronic itching. There are many pathways leading from BRAF, and all of these could be potential targets for anti-itch therapies.”

About a dozen years ago, scientists discovered that a hormone called ghrelin enhances appetite. Dubbed the “hunger hormone,” ghrelin was quickly targeted by drug companies seeking treatments for obesity — none of which have yet panned out.

MIT neuroscientists have now discovered that ghrelin’s role goes far beyond controlling hunger. The researchers found that ghrelin released during chronic stress makes the brain more vulnerable to traumatic events, suggesting that it may predispose people to posttraumatic stress disorder (PTSD).

Drugs that reduce ghrelin levels, originally developed to try to combat obesity, could help protect people who are at high risk for PTSD, such as soldiers serving in war, says Ki Goosens, an assistant professor of brain and cognitive sciences at MIT, and senior author of a paper describing the findings in the Oct. 15 online edition of Molecular Psychiatry.

“Perhaps we could give people who are going to be deployed into an active combat zone a ghrelin vaccine before they go, so they will have a lower incidence of PTSD. That’s exciting because right now there’s nothing given to people to prevent PTSD,” says Goosens, who is also a member of MIT’s McGovern Institute for Brain Research.

Lead author of the paper is Retsina Meyer, a recent MIT PhD recipient. Other authors are McGovern postdoc Anthony Burgos-Robles, graduate student Elizabeth Liu, and McGovern research scientist Susana Correia.

Stress and fear

Stress is a useful response to dangerous situations because it provokes action to escape or fight back. However, when stress is chronic, it can produce anxiety, depression and other mental illnesses.

At MIT, Goosens discovered that one brain structure that is especially critical for generating fear, the amygdala, has a special response to chronic stress. The amygdala produces large amounts of growth hormone during stress, a change that seems not to occur in other brain regions.

In the new paper, Goosens and her colleagues found that the release of the growth hormone in the amygdala is controlled by ghrelin, which is produced primarily in the stomach and travels throughout the body, including the brain.

Ghrelin levels are elevated by chronic stress. In humans, this might be produced by factors such as unemployment, bullying, or loss of a family member. Ghrelin stimulates the secretion of growth hormone from the brain; the effects of growth hormone from the pituitary gland in organs such as the liver and bones have been extensively studied. However, the role of growth hormone in the brain, particularly the amygdala, is not well known.

The researchers found that when rats were given either a drug to stimulate the ghrelin receptor or gene therapy to overexpress growth hormone over a prolonged period, they became much more susceptible to fear than normal rats. Fear was measured by training all of the rats to fear an innocuous, novel tone. While all rats learned to fear the tone, the rats with prolonged increased activity of the ghrelin receptor or overexpression of growth hormone were the most fearful, assessed by how long they froze after hearing the tone. Blocking the cell receptors that interact with ghrelin or growth hormone reduced fear to normal levels in chronically stressed rats.

When rats were exposed to chronic stress over a prolonged period, their circulating ghrelin and amygdalar growth hormone levels also went up, and fearful memories were encoded more strongly. This is similar to what the researchers believe happens in people who suffer from PTSD.

“When you have people with a history of stress who encounter a traumatic event, they are more likely to develop PTSD because that history of stress has altered something about their biology. They have an excessively strong memory of the traumatic event, and that is one of the things that drives their PTSD symptoms,” Goosens says.

New drugs, new targets

Over the last century, scientists have described the hypothalamic-pituitary-adrenal (HPA) axis, which produces adrenaline, cortisol (corticosterone in rats), and other hormones that stimulate “fight or flight” behavior. Since then, stress research has focused almost exclusively on the HPA axis.

After discovering ghrelin’s role in stress, the MIT researchers suspected that ghrelin was also linked to the HPA axis. However, they were surprised to find that when the rats’ adrenal glands — the source of corticosterone, adrenaline, and noradrenaline — were removed, the animals still became overly fearful when chronically stressed. The authors also showed that repeated ghrelin-receptor stimulation did not trigger release of HPA hormones, and that blockade of the ghrelin receptor did not blunt release of HPA stress hormones. Therefore, the ghrelin-initiated stress pathway appears to act independently of the HPA axis. “That’s important because it gives us a whole new target for stress therapies,” Goosens says.

Pharmaceutical companies have developed at least a dozen possible drug compounds that interfere with ghrelin. Many of these drugs have been found safe for humans, but have not been shown to help people lose weight. The researchers believe these drugs could offer a way to vaccinate people entering stressful situations, or even to treat people who already suffer from PTSD, because ghrelin levels remain high long after the chronic stress ends.

PTSD affects about 7.7 million American adults, including soldiers and victims of crimes, accidents, or natural disasters. About 40 to 50 percent of patients recover within five years, Meyer says, but the rest never get better.

The researchers hypothesize that the persistent elevation of ghrelin following trauma exposure could be one of the factors that maintain PTSD. “So, could you immediately reverse PTSD? Maybe not, but maybe the ghrelin could get damped down and these people could go through cognitive behavioral therapy, and over time, maybe we can reverse it,” Meyer says.

Working with researchers at Massachusetts General Hospital, Goosens’ lab is now planning to study ghrelin levels in human patients suffering from anxiety and fear disorders. They are also planning a clinical trial of a drug that blocks ghrelin to see if it can prevent relapse of depression.

Scientists at the University of Washington have used genetic engineering to identify a population of neurons that tell the brain to shut off appetite. Their study, “Genetic identification of a neural circuit that suppresses appetite,” was published Oct. 13 in Nature.

To identify these neurons, or cells that process and transmit information in the brain, researchers first considered what makes an animal lose its appetite. There are a number of natural reasons, including infection, nausea, pain or simply having eaten too much already.

Nerves within the gut that are distressed or insulted send information to the brain through the vagus nerve. Appetite is suppressed when these messages activate specific neurons – ones that contain CGRP, (calcitonin gene-related peptide) in a region of the brain called the parabrachial nucleus.

In mouse trials, researchers used genetic techniques and viruses to introduce light-activatable proteins into CGRP neurons. Activation of these proteins excites the cells to transmit chemical signals to other regions of the brain. When they activated the CGRP neurons with a laser, the hungry mice immediately lost their appetite and walked away from their liquid diet (Ensure); when the laser was turned off, the mice resumed drinking the liquid diet.

"These results demonstrate that activation of the CGRP-expressing neurons regulates appetite. This is a nice example of how the brain responds to unfavorable conditions in the body, such as nausea caused by food poisoning" said Richard Palmiter, UW professor of biochemistry and investigator of the Howard Hughes Medical Institute.

Using a similar approach, neurons in other brain regions have been identified that can stimulate the appetite of mice that are not hungry. Researchers hope to identify the complete neural circuit (wiring diagram) in the brain that regulates feeding behavior. By identifying these neural circuits, scientists may be able to design therapies that promote or decrease appetite.

The brain is plastic - adapting to the hundreds of experiences in our daily lives by reorganizing pathways and making new connections between nerve cells. This plasticity requires that memories of new information and experiences are formed fast. So fast that the body has a special mechanism, unique to nerve cells, that enables memories to be made rapidly. In a new study from The Montreal Neurological Institute and Hospital, The Neuro, McGill University with colleagues at the Université de Montréal, researchers have discovered that nerve cells have a special ‘pre-assembly’ technique to expedite the manufacture of proteins at nerve cell connections (synapses), enabling the brain to rapidly form memories and be plastic.

Making a memory requires the production of proteins at synapses. These proteins then change the strength of the connection or pathway. In nerve cells the production process for memory proteins is already pre-assembled at the synapse but stalled just before completion, awaiting the proper signals to finish, thereby speeding up the entire process. When it comes time to making the memory, the process is switched on and the protein is made in a flash. The mechanism is analogous to a pre-fab home, or pre-made pancake batter that is assembled in advance and then quickly completed in the correct location at the correct time.

“It’s not only important to make proteins in the right place but, it’s also important not to make the protein when it’s the wrong time,” says Dr. Wayne Sossin, neuroscientist at The Neuro and senior investigator on the paper. “This is especially important with nerve cells in the brain, as you only want the brain to make precise connections. If this process is indiscriminate, it leads to neurological disease. This mechanism to control memory protein synthesis solves two problems: 1) how to make proteins only at the right time and 2) how to make proteins as quickly as possible in order to tightly associate the synaptic change with the experience/memory.

Making proteins from genetic material involves two major steps [a Nobel prize was awarded for the identification of the cell’s protein-making process]. In the first step, called transcription, the information in DNA that is stored and protected within the centre of the cell is copied to a messenger RNA (mRNA) – this copy is then moved to where it is needed in the cell. In the second step, called translation, the mRNA is used as a template of genetic information and ‘read’ by little machines called ribosomes, which decode the mRNA sequence and stitch together the correct amino acids to form the protein.

Dr. Sossin’s group at The Neuro has discovered that the mRNA travels to the synapse already attached to the ribosome, with the protein production process stopped just before completion of the product (at the elongation/termination step of translation, where amino acids are being assembled into protein). The ‘pre-assembly’ process then waits for synaptic signals before re-activating to produce a lot of proteins quickly in order to form a memory. “Our results reveal a new mechanism underlying translation-dependent synaptic plasticity, which is dysregulated in neurodevelopmental and psychiatric pathologies”, added Dr. Sossin. “Understanding the pathways involved may provide new therapeutic targets for neurodevelopmental disorders. “

A brain region activated when people are asked to perform mathematical calculations in an experimental setting is similarly activated when they use numbers — or even imprecise quantitative terms, such as “more than”— in everyday conversation, according to a study by Stanford University School of Medicine scientists.

Using a novel method, the researchers collected the first solid evidence that the pattern of brain activity seen in someone performing a mathematical exercise under experimentally controlled conditions is very similar to that observed when the person engages in quantitative thought in the course of daily life.

“We’re now able to eavesdrop on the brain in real life,” said Josef Parvizi, MD, PhD, associate professor of neurology and neurological sciences and director of Stanford’s Human Intracranial Cognitive Electrophysiology Program. Parvizi is the senior author of the study, published Oct. 15 in Nature Communications. The study’s lead authors are postdoctoral scholar Mohammad Dastjerdi, MD, PhD, and graduate student Muge Ozker.

The finding could lead to “mind-reading” applications that, for example, would allow a patient who is rendered mute by a stroke to communicate via passive thinking. Conceivably, it could also lead to more dystopian outcomes: chip implants that spy on or even control people’s thoughts.

“This is exciting, and a little scary,” said Henry Greely, JD, the Deane F. and Kate Edelman Johnson Professor of Law and steering committee chair of the Stanford Center for Biomedical Ethics, who played no role in the study but is familiar with its contents and described himself as “very impressed” by the findings. “It demonstrates, first, that we can see when someone’s dealing with numbers and, second, that we may conceivably someday be able to manipulate the brain to affect how someone deals with numbers.”

The researchers monitored electrical activity in a region of the brain called the intraparietal sulcus, known to be important in attention and eye and hand motion. Previous studies have hinted that some nerve-cell clusters in this area are also involved in numerosity, the mathematical equivalent of literacy.

However, the techniques that previous studies have used, such as functional magnetic resonance imaging, are limited in their ability to study brain activity in real-life settings and to pinpoint the precise timing of nerve cells’ firing patterns. These studies have focused on testing just one specific function in one specific brain region, and have tried to eliminate or otherwise account for every possible confounding factor. In addition, the experimental subjects would have to lie more or less motionless inside a dark, tubular chamber whose silence would be punctuated by constant, loud, mechanical, banging noises while images flashed on a computer screen.

“This is not real life,” said Parvizi. “You’re not in your room, having a cup of tea and experiencing life’s events spontaneously.” A profoundly important question, he said, is: “How does a population of nerve cells that has been shown experimentally to be important in a particular function work in real life?”

His team’s method, called intracranial recording, provided exquisite anatomical and temporal precision and allowed the scientists to monitor brain activity when people were immersed in real-life situations. Parvizi and his associates tapped into the brains of three volunteers who were being evaluated for possible surgical treatment of their recurring, drug-resistant epileptic seizures.

The procedure involves temporarily removing a portion of a patient’s skull and positioning packets of electrodes against the exposed brain surface. For up to a week, patients remain hooked up to the monitoring apparatus while the electrodes pick up electrical activity within the brain. This monitoring continues uninterrupted for patients’ entire hospital stay, capturing their inevitable repeated seizures and enabling neurologists to determine the exact spot in each patient’s brain where the seizures are originating.

During this whole time, patients remain tethered to the monitoring apparatus and mostly confined to their beds. But otherwise, except for the typical intrusions of a hospital setting, they are comfortable, free of pain and free to eat, drink, think, talk to friends and family in person or on the phone, or watch videos.

The electrodes implanted in patients’ heads are like wiretaps, each eavesdropping on a population of several hundred thousand nerve cells and reporting back to a computer.

In the study, participants’ actions were also monitored by video cameras throughout their stay. This allowed the researchers later to correlate patients’ voluntary activities in a real-life setting with nerve-cell behavior in the monitored brain region.

As part of the study, volunteers answered true/false questions that popped up on a laptop screen, one after another. Some questions required calculation — for instance, is it true or false that 2+4=5? — while others demanded what scientists call episodic memory — true or false: I had coffee at breakfast this morning. In other instances, patients were simply asked to stare at the crosshairs at the center of an otherwise blank screen to capture the brain’s so-called “resting state.”

Consistent with other studies, Parvizi’s team found that electrical activity in a particular group of nerve cells in the intraparietal sulcus spiked when, and only when, volunteers were performing calculations.

Afterward, Parvizi and his colleagues analyzed each volunteer’s daily electrode record, identified many spikes in intraparietal-sulcus activity that occurred outside experimental settings, and turned to the recorded video footage to see exactly what the volunteer had been doing when such spikes occurred.

They found that when a patient mentioned a number — or even a quantitative reference, such as “some more,” “many” or “bigger than the other one” — there was a spike of electrical activity in the same nerve-cell population of the intraparietal sulcus that was activated when the patient was doing calculations under experimental conditions.

That was an unexpected finding. “We found that this region is activated not only when reading numbers or thinking about them, but also when patients were referring more obliquely to quantities,” said Parvizi.

“These nerve cells are not firing chaotically,” he said. “They’re very specialized, active only when the subject starts thinking about numbers. When the subject is reminiscing, laughing or talking, they’re not activated.” Thus, it was possible to know, simply by consulting the electronic record of participants’ brain activity, whether they were engaged in quantitative thought during nonexperimental conditions.

Any fears of impending mind control are, at a minimum, premature, said Greely. “Practically speaking, it’s not the simplest thing in the world to go around implanting electrodes in people’s brains. It will not be done tomorrow, or easily, or surreptitiously.”

Parvizi agreed. “We’re still in early days with this,” he said. “If this is a baseball game, we’re not even in the first inning. We just got a ticket to enter the stadium.”

Neurons that process sensory information such as touch and vision are arranged in precise, well-characterized maps that are crucial for translating perception into understanding. A study published by Cell Press on October 14 in the journal Developmental Cell reveals that the actual act of birth in mice causes a reduction in a brain chemical called serotonin in the newborn mice, triggering sensory maps to form. The findings shed light on the key role of a dramatic environmental event in the development of neural circuits and reveal that birth itself is one of the triggers that prepares the newborn for survival outside the womb.

"Our results clearly demonstrate that birth has active roles in brain formation and maturation," says senior study author Hiroshi Kawasaki of Kanazawa University in Japan. "We found that birth regulates neuronal circuit formation not only in the somatosensory system but also in the visual system. Therefore, it seems reasonable to speculate that birth actually plays a wider role in various brain regions."

Mammals ranging from mice to humans have brain maps that represent various types of sensory information. In a region of the rodent brain known as the barrel cortex, neurons that process tactile information from whiskers are arranged in a map corresponding to the spatial pattern of whiskers on the snout, with neighboring columns of neurons responding to stimulation of adjacent whiskers. Although previous studies have shown that the neurotransmitter serotonin influences the development of sensory maps, its specific role during normal development has not been clear until now.

In this new study, Kawasaki and his team find that the birth of mouse pups leads to a drop in serotonin levels in the newborn’s brain, triggering the formation of neural circuits in the barrel cortex and in the lateral geniculate nucleus (LGN), a brain region that processes visual information. When mice were treated with drugs that either induced preterm birth or decreased serotonin signaling, neural circuits in the barrel cortex as well as in the LGN formed more quickly. Conversely, neural circuits in the barrel cortex failed to form when the mice were treated with a drug that increased serotonin signaling, suggesting that a reduction in levels of this neurotransmitter is crucial for sensory map formation.

Because serotonin also plays a key role in mental disorders, it is possible that abnormalities in birth processes and the effects on subsequent serotonin signaling and brain development could increase the risk of psychiatric diseases. “Uncovering the entire picture of the downstream signaling pathways of birth may lead to the development of new therapeutic methods to control the risk of psychiatric diseases induced by abnormal birth,” Kawasaki says.

Faced with news of suicides and brain damage in former professional football players, geneticist Barry Ganetzky bemoaned the lack of model systems for studying the insidious and often delayed consequences linked to head injuries.

Then he remembered an unexplored observation from nearly 40 years ago: a sharp strike to a vial of fruit flies left them temporarily stunned, only to recover a short time later. At the time he had marked it only as a curiosity.

Now a professor of genetics at UW–Madison, Ganetzky is turning his accidental discovery into a way to study traumatic brain injury (TBI). He and David Wassarman, a UW professor of cell and regenerative biology, report this week (Oct. 14) in the Proceedings of the National Academy of Sciences on the first glimpses of the genetic underpinnings of susceptibility to brain injuries and links to human TBI.

TBIs occur when a force on the body jostles the brain inside the head, causing it to strike the inside of the skull. More than 1.7 million TBIs occur each year in the United States, about one-third due to falls and the rest mainly caused by car crashes, workplace accidents, and sports injuries. TBIs are also a growing issue in combat veterans exposed to explosions.

In many cases, the immediate effects of TBI are temporary and may seem mild — confusion, dizziness or loss of coordination, headaches, vision problems. But over time, impacts may lead to neurodegeneration and related symptoms, including memory loss, cognitive problems, severe depression, or Alzheimer’s-like dementia. Together TBIs cost tens of billions of dollars annually in medical expenses and indirect costs such as lost productivity.

Though TBIs can be classified from “mild” to “severe” based on symptoms, there is a poor understanding of the underlying medical causes.

“Unlike many important medical problems — high blood pressure, cancer, diabetes, heart disease — where we know something about the biology, we know almost nothing about TBI,” Ganetzky says. “Why does a blow to the head cause epilepsy? Or how does it lead down the road to neurodegeneration? Nobody has answers to those questions — in part, because it’s really hard to study in humans.”

Enter the fruit fly. The fly brain is encased in a hard cuticle analogous to the skull, and the basic mechanisms affecting nervous system function are the same in flies and mammals. In the new study, Ganetzky and Wassarman describe a way to reproducibly inflict traumas that seem to mimic the injuries and symptoms of human TBI.

“Now we have a system where we can look at the variables that are the inputs into TBI and determine the relative contributions of each to the pathological outcomes. That’s the real power of the flies,” says Wassarman.

As with humans, few flies die from the immediate impact. Afterward, though, the treated flies show many of the same physical consequences as humans who sustain concussions or other TBIs, including temporary incapacitation, loss of coordination and activation of the innate immune response in the short term, followed by neurodegeneration and sometimes an early death.

The researchers, led by Rebeccah Katzenberger, senior research specialist in the UW Department of Cell and Regnerative Biology, also found that age seems to play an important role. Older flies are more susceptible than younger ones to the effects of the impact and, Wassarman says, many of the outcomes of TBI are very similar to normal aging processes.

With this model, the researchers say, they can now draw on the vast collection of genetic tools and techniques available for fruit flies to probe the underlying drivers of damage.

“What we really want is to understand the immediate and long term consequences in cellular and molecular terms,” says Ganetzky. “From that understanding we can proceed in a more directed way to diagnostics and therapeutics.”

One of the key things they have already identified is the crucial role genetics plays in determining the outcome of an injury, revealed by the high degree of variability seen among different strains of flies. This finding may explain why all potential TBI drugs to date have failed in clinical trials despite showing promise in individual rodent models.

As Wassarman explains, “The heart of the problem of solving traumatic brain injury is that we’re all different.”

They are continuing to develop the model through large-scale genetic analysis and have already found that different sets of genes correlate with susceptibility in flies of different ages. With their system, they can also examine the effects of repeated injuries.

Ganetzky sees tremendous potential for developing applications from the fly-based approach and the Wisconsin Alumni Research Foundation (WARF) has filed for patent protection on the discovery.

“These exciting findings that we can study traumatic brain injury — a disorder of growing concern for athletes, the military, and parents — in the elegantly simple model of fruit flies is sure to interest those researchers and companies looking to address this concern,” says Jennifer Gottwald, WARF licensing manager. “The use of this model can accelerate the work of the medical research community in finding treatments and therapies to help patients.”

Recent scientific findings have raised the fear that young athletes may fare worse after sustaining a sports-related concussion than older athletes.

Researchers in the Vanderbilt Sports Concussion Center compared symptoms associated with concussion in middle- and high-school aged athletes with those in college-age athletes and found no significant differences between the two age groups.

The study, “Does age affect symptom recovery after sports-related concussion? A study of high school and college athletes,” was published online Sept. 24 ahead of print in the Journal of Neurosurgery: Pediatrics.

Lead authors were Vanderbilt University School of Medicine students Young Lee and Mitchell Odom. Other researchers were Scott Zuckerman, M.D., Gary Solomon, Ph.D., and Allen Sills, M.D.

In this retrospective study, the researchers reviewed a database containing information on pre-concussion and post-concussion symptoms in two different age groups: younger (13-16 years old) and older (18-22 years old). Athletes (92 in each group) were evenly matched with respect to gender, number of previous concussions, and time to the first post-concussion test.

Each athlete completed individual pre- and post-concussion questionnaires that covered a variety of symptoms associated with concussion, some of which were headache, nausea, dizziness, fatigue, sleep problems, irritability and difficulties with concentration or memory. Each athlete’s post-concussion scores were compared to his or her own individual baseline scores.

The number or severity of symptoms cited at baseline and post-concussion showed no significant difference between the two age groups. Symptoms returned to baseline levels within 30 days after concussion in 95.7 percent of the younger athletes and in 96.7 percent of the older athletes.

“In the evaluation of sports-related concussion, it is imperative to parse out different ways of assessing outcomes: neurocognitive scores versus symptom endorsement versus balance issues, school performance, etc,” Zuckerman said.

“It appears that symptoms may not be a prominent driver when assessing outcomes of younger versus older athletes. We hope that our study can add insight into the evaluation of youth athletes after sports-related concussion.”