Neuroscience

Survivors of traumatic brain injuries (TBI) are three times more likely to die prematurely than the general population, often from suicide or fatal injuries, finds an Oxford University-led study.

A TBI is a blow to the head that leads to a skull fracture, internal bleeding, loss of consciousness for longer than an hour or a combination of these symptoms. Michael Schumacher’s recent skiing injury is an example of a TBI. Concussions, sometimes called mild TBIs, do not present with these symptoms and were analysed separately in this study.

Researchers examined Swedish medical records going back 41 years covering 218,300 TBI survivors, 150,513 siblings of TBI survivors and over two million control cases matched by sex and age from the general population. The work was carried out by researchers at Oxford University and the Karolinska Institute in Stockholm.

'We found that people who survive six months after TBI remain three times more likely to die prematurely than the control population and 2.6 times more likely to die than unaffected siblings,' said study leader Dr Seena Fazel, a Wellcome Trust Senior Research Fellow in Oxford University's Department of Psychiatry. 'Looking at siblings who did not suffer TBIs allows us to control for genetic factors and early upbringing, so it is striking to see that the effect remains strong even after controlling for these.'

The results, published in the journal JAMA Psychiatry, show that TBI survivors who also have a history of substance abuse or psychiatric disorders are at highest risk of premature death. Premature deaths were defined as before age 56. The main causes of premature death in TBI survivors are suicide and fatal injuries such as car accidents and falls.

'TBI survivors are more than twice as likely to kill themselves as unaffected siblings, many of whom were diagnosed with psychiatric disorders after their TBI,' said Dr Fazel. 'Current guidelines do not recommend assessments of mental health or suicide risk in TBI patients, instead focusing on short-term survival. Looking at these findings, it may make more sense to treat some TBI patients as suffering from a chronic problem requiring longer term management just like epilepsy or diabetes. TBI survivors should be monitored carefully for signs of depression, substance abuse and other psychiatric disorders, which are all treatable conditions.'

The exact reasons for the increased risk of premature death are unknown but may involve damage to the parts of the brain responsible for judgement, decision making and risk taking. TBI survivors are three times more likely to die from fatal injuries which may be a result of impaired judgement or reactions.

'This study highlights the important and as yet unanswered question of why TBI survivors are more likely to die young, but it may be that serious brain trauma has lasting effects on people's judgement,' suggests Dr Fazel. 'People who have survived the acute effects of TBI should be more informed about these risks and how to reduce their impact.'

'When treating traumatic brain injuries focus is placed on immediate treatment and recovery of patients,' says Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust. 'This new finding offers important insight into the longer-term impact of TBIs on the brain and their effect on survival later in life. We hope that further research into understanding which parts of the brain are responsible will help improve future management programmes and reduce the potential for premature death.'

Even relatively minor brain injuries, concussions, had a significant impact on early mortality. People with concussion were found to be twice as likely to die prematurely as the control population, with suicide and fatal injuries as the main causes of death. This raises issues surrounding concussions in a wide range of sports, from American football, rugby and soccer to baseball and cricket.

We use both sides of our brain for speech, a finding by researchers at New York University and NYU Langone Medical Center that alters previous conceptions about neurological activity. The results, which appear in the journal Nature, also offer insights into addressing speech-related inhibitions caused by stroke or injury and lay the groundwork for better rehabilitation methods.

“Our findings upend what has been universally accepted in the scientific community—that we use only one side of our brains for speech,” says Bijan Pesaran, an associate professor in NYU’s Center for Neural Science and the study’s senior author. “In addition, now that we have a firmer understanding of how speech is generated, our work toward finding remedies for speech afflictions is much better informed.”

Many in the scientific community have posited that both speech and language are lateralized—that is, we use only one side of our brains for speech, which involves listening and speaking, and language, which involves constructing and understanding sentences. However, the conclusions pertaining to speech generally stem from studies that rely on indirect measurements of brain activity, raising questions about characterizing speech as lateralized.

To address this matter, the researchers directly examined the connection between speech and the neurological process.

Specifically, the study relied on data collected at NYU ECoG, a center where brain activity is recorded directly from patients implanted with specialized electrodes placed directly inside and on the surface of the brain while the patients are performing sensory and cognitive tasks. Here, the researchers examined brain functions of patients suffering from epilepsy by using methods that coincided with their medical treatment.

“Recordings directly from the human brain are a rare opportunity,” says Thomas Thesen, director of the NYU ECoG Center and co-author of the study.

“As such, they offer unparalleled spatial and temporal resolution over other imaging technologies to help us achieve a better understanding of complex and uniquely human brain functions, such as language,” adds Thesen, an assistant professor at NYU Langone.

In their examination, the researchers tested the parts of the brain that were used during speech. Here, the study’s subjects were asked to repeat two “non-words”—“kig” and “pob.” Using non-words as a prompt to gauge neurological activity, the researchers were able to isolate speech from language.

An analysis of brain activity as patients engaged in speech tasks showed that both sides of the brain were used—that is, speech is, in fact, bi-lateral.

“Now that we have greater insights into the connection between the brain and speech, we can begin to develop new ways to aid those trying to regain the ability to speak after a stroke or injuries resulting in brain damage,” observes Pesaran. “With this greater understanding of the speech process, we can retool rehabilitation methods in ways that isolate speech recovery and that don’t involve language.”

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have described a pair of drug candidates that advance the search for new treatments for pain, addiction and other disorders.

The two new drug scaffolds, described in a recent edition of The Journal of Biological Chemistry, offer researchers novel tools that act on a demonstrated therapeutic target, the kappa opioid receptor (KOR), which is located on nerve cells and plays a role in the release of the neurotransmitter dopamine. While compounds that activate KOR are associated with positive therapeutic effects, they often also recruit a molecule known as βarrestin2 (beta arrestin), which is associated with depressed mood and severely limits any therapeutic potential.

“Compounds that act at kappa receptors may provide a means for treating addiction and for treating pain; however, there is the potential for the development of depression or dysphoria associated with this receptor target,” said Laura Bohn, a TSRI associate professor who led the study. “There is evidence that the negative feelings caused by kappa receptor drugs may be, in part, due to receptor actions through proteins called beta arrestins. Developing compounds that activate the receptors without recruiting beta arrestin function may serve as a means to improve the therapeutic potential and limit side effects.”

The new compounds are called “biased agonists,” activating the receptor without engaging the beta arrestins.

Research Associate Lei Zhou, first author of the study with Research Associate Kimberly M. Lovell, added, “The importance of these biased agonists is that we can manipulate the activation of one particular signaling cascade that produces analgesia, but not the other one that could lead to dysphoria or depression.”

The researchers note that the avoidance of depression is particularly important in addiction treatment, where depressed mood can play a role in relapse. 

The two drug candidates also have a high affinity and selectivity for KOR over other opioid receptors and are able to pass through the blood-brain barrier. Given these promising attributes, the scientists plan to continue developing the compounds.

When an MRI scan uncovers an unusual architecture or shape in a child’s brain, it’s cause for concern: The malformation may be a sign of disease. But deciding whether that odd-looking anatomy is worrisome or harmless can be difficult. To help doctors reach the right decision, Johns Hopkins researchers are building a detailed digital library of MRI scans collected from children with normal and abnormal brains. The goal, the researchers say, is to give physicians a Google-like search system that will enhance the way they diagnose and treat young patients with brain disorders.

This cloud-computing project, being developed by a team of engineers and radiologists, should allow physicians to access thousands of pediatric scans to look for some that resemble their own patient’s image. The project is supported by a three-year $600,000 grant from the National Institutes of Health.

"We’re creating a pediatric brain data bank that will let doctors look at MRI brain scans of children who have already been diagnosed with illnesses like epilepsy or psychiatric disorders," said Michael I. Miller, a lead investigator on the project. "It will provide a way to share important new discoveries about how changes in brain structures are linked to brain disorders. For the medical imaging world, this system will do what a search engine like Google does when you ask it to look for specific information on the Web."

Miller, a pioneer in the field of computational anatomy, the technology used for “brain parsing,” is the Herschel and Ruth Seder Professor of Biomedical Engineering at Johns Hopkins and director of the university’s Center for Imaging Science. He also is a core faculty member in the university’s Institute for Computational Medicine.

The new pediatric brain imaging data bank, Miller said, will be useful in at least two ways.

"If doctors aren’t sure which disease is causing a child’s condition, they could search the data bank for images that closely match their patient’s most recent scan," he said. "If a diagnosis is already attached to an image from the data bank that could steer the physician in the right direction. Also, the scans in our library may help a physician identify a change in the shape of a brain structure that occurs very early in the course of a disease, even before clinical symptoms appear. That could allow the physician get an early start on the treatment."

Miller’s co-lead investigator on the project is Susumu Mori, a professor of radiology in the Johns Hopkins School of Medicine. One of Mori’s primary research interests is studying the anatomy of brain structures captured in MRI scans. 

Mori points out that such a “biobank” has the potential to impact doctors’ workflow dramatically.

"We empirically know that a certain type of anatomical abnormality is related to specific brain diseases," he said. "This relationship, however, is not always clear and often is compounded by anatomical changes during the normal course of brain development. Therefore, neuro-radiologists need extensive training to accumulate the knowledge. We hope our brain imaging data bank will not only assist such a learning process but also enhance the physician’s ability to understand the pathology and reach the best medical decision."

Mori and his collaborator, Thierry Huisman, a professor of radiology and pediatrics and the director of pediatric radiology at the Johns Hopkins Children’s Center, have been working for more than four years to establish a clinical database of more than 5,000 whole-brain MRI scans of children treated at Johns Hopkins. The patients’ names and other identifying information were withheld, but details related to their medical conditions were included. The computer software indexed anatomical information involving up to 1,000 structural measurements in 250 regions of the brain. These images were also sorted into 22 brain disease categories, including chromosomal abnormalities, congenital malformations, vascular diseases, infections, epilepsy and psychiatric disorders.

According to Huisman, the new data bank now under development not only facilitates recognition and correct classification of pediatric brain disorders, but the more objective image analysis also allows identification of injury and disease that may go undetected by the classical, more subjective radiological “eyeballing” of MR images. Furthermore, he said, recognition of distinct patterns of injury and the subsequent grouping of these children based upon their characteristic patterns of MRI findings allow recognition and identification of new diseases as well as reclassification of previously unclassified diseases. Finally, he added, the data acquisition is free of ionizing radiation, allowing doctors to study the most vulnerable, youngest patients and perhaps to help initiate disease-specific treatment before irreversible injury to the developing brain occurs.

Beyond the brain imaging data bank for children, the researchers have begun building a similar MRI brain image library with Marilyn Albert, a Johns Hopkins neurology professor. This library focuses on brain disorders commonly found in elderly patients. That project is associated with the National Institute of Aging’ Alzheimer’s Disease Research Center.

With all of this data in place, physicians will be able to conduct a Google-like search for images associated with normal and abnormal pediatric and aging brain conditions. For example, a physician who is uncertain about a child’s diagnosis could submit that patient’s latest brain scan and request the medical records of children with similar images. Alternatively, for studying neurodegenerative diseases such as Alzheimer’s in aging patients, a physician might ask to see the medical records associated with all images that display neurofibrillary tangles in the temporal lobe, a condition seen in his or her patient’s scan.

Jonathan Lewin, the chairman and radiologist-in-chief of the Johns Hopkins Department of Radiology and Radiological Science, noted that this approach could help patients with both common and uncommon diseases. “This research is one of the first real applications of ‘Big Data’ analytics, taking medical information from large numbers of patients, removing anything that would identify specific individuals, and then bringing the data into the ‘cloud’ to allow very high-powered analysis,” Lewin said. “This has been a goal of the medical community for almost a decade, and professors Miller and Mori have found a way to implement this technology in a manner that can bring its benefit to our patients, and can assist in the classification and identification of rare and subtle brain disorders as well as uncommon manifestations of more common diseases of the brain.”

Currently, the pilot pediatric brain imaging data bank is limited to physicians and patients within the Johns Hopkins medical system, but the researchers say the data bank could be expanded or replicated elsewhere in coming years.

A new form of cell sub-division that is key to the development of the nervous system has been identified by researchers at the University of Dundee.

Image caption: Image shows two newborn neurons shedding their tip ends, or abscising

Neurons are vital to the development of the nervous system and in some regions of our brains they are continually produced throughout our lives. They are ‘born’ in a particular place in the early nervous system and then have to migrate to the correct place to make functional neural structures.

A team led by Professor Kate Storey and Dr Raman Das in the College of Life Sciences at Dundee have now identified a new process, apical abscission, which mediates the detachment of new-born neurons from the neural tube ventricle - freeing these cells to migrate.

'Neuron production is an important process within our bodies. As an example, our memory centre, the hippocampus, continues to produce neurons throughout our lives,' said Professor Storey.

'What we have identified are the molecular events, the 'letting-go' process, which allow newborn neurons to move to their correct place in the nervous system.

'This is a new form of cell sub-division so it is of significant interest as it tells us about mechanisms that control how we develop that we didn't know before. We were very surprised when we first saw cells shedding their tip-ends as they began to differentiate into neurons, it is not what we had expected at all.

'Our discovery comes with the development of novel live-tissue imaging approaches in my lab, which allows us to monitor cell behaviour over long periods. We have also been to make use of state of the art super-resolution microscopy in the Light Microscopy Facility based here within the College of Life Sciences.'

The research has been funded by the Wellcome Trust and the results are published this week in the journal Science.

The work identifies molecular events that control the shedding of the cell’s tip. It takes place as cells lose a key adhesion molecule and involves increased activity of a cell constriction mechanism.

Surprisingly, this event, also involves dismantling of an important structure in the cell, the primary cilium, known to convey signals that promote cell proliferation. Das and Storey propose that Apical Abscission mediates a pivotal cell state transition in the neuronal differentiation process, rapidly altering the polarity and signalling activity of the new-born neuron.

The researchers plan to extend the work to determine if this new mechanism also operates in other contexts including different regions of the brain, but will also address if this takes place in some cancers, where cells are known to lose polarity, shed primary cilia and detach from their neighbours as a prelude to tissue invasion.

'We need to look more widely now to establish whether this regulated mechanism allows other cells to make rapid cell state transitions and to move in other tissues of the body,' said Professor Storey.

Producing brightly speckled red and green snapshots of many different tissues, Johns Hopkins researchers have color-coded cells in female mice to display which of their two X chromosomes has been made inactive, or “silenced.”

(Image caption: Patterns of X chromosome silencing in cells of the cornea, skin, cartilage and inner ear of mice (clockwise). Cells are red or green depending on whether they have inactivated their maternal or paternal X chromosome, respectively. Hao Wu, courtesy of Neuron)

Scientists have long known that the silencing of one X chromosome in females — who have two X chromosomes in every cell — is a normal occurrence whose consequences can be significant, especially if one X chromosome carries a normal copy of a gene and the other X chromosome carries a mutated copy.

By genetically tagging different X chromosomes with genes that code for red or green fluorescent proteins, scientists say they can now peer into different tissue types to analyze genetic diversity within and between individual females at a new level of detail.

Published on Jan. 8 in the journal Neuron, a summary of the research shows wide-ranging variation in patterns of so-called X chromosome inactivation at every level: within tissues, on the left or right sides of a centrally located tissue (like the brain), among different tissue types, between paired organs (like the eyes) and among individuals.

"Calico cats, which are only ever female, have mottled coat colors. They have two different versions of a gene for coat color, which is located on the X chromosome: one version from their mother and the other from their father," explains Jeremy Nathans, M.D., Ph.D., professor of molecular biology and genetics at the Johns Hopkins University and a Howard Hughes Medical Institute investigator. "Their fur is orange or black depending on which X chromosome is silenced in a particular patch of skin cells. X chromosome inactivation actually occurs in all cells in female mammals, including humans, and it affects most of the genes on the X chromosome. Although this phenomenon has been known for over 50 years, it couldn’t be clearly visualized in internal organs and tissues until now."

Nathans adds that early in the development of most mammals, when a female embryo has only about 1,000 cells, each cell makes a “decision” to inactivate one of the two X chromosomes, a process that silences most of the genes on that chromosome. The choice of which X chromosome to inactivate appears to be random, but when those cells divide, their descendants maintain that initial decision.

In the new research, the Johns Hopkins team mated female mice carrying two copies of the gene for green fluorescent protein — one on each of the two X chromosomes — with male mice whose single X chromosome carried the gene for a red fluorescent protein. The female offspring from this mating had cells that glowed red or green based on which X chromosome was silenced. Additionally, the team engineered the mice so that not all of their cells were color-coded, since that would make it hard to distinguish one cell from another. Instead, they designed a system that allowed a single cell type in each mouse, such as heart muscle cells, to be color-coded. Their genetic trick resulted in red and green color maps with distinctive patterns for each cell and tissue type that they examined.

Nathans explains that the patterns are determined by the way each tissue develops. Some tissues are created from a very small number of “founder cells” in the early embryo; others are created from a large number. Statistically, the larger the group of founder cells, the greater the chances are of having a nearly equivalent number of red and green cells. Although the ratio in the founding group is roughly preserved as the tissue grows, the distribution of those cells is determined by how much movement occurs during the development of the tissue. For example, in a tissue like blood, where the cells move a lot, the red and green cells are finely intermingled. By contrast, in skin, where the cells show little movement, each patch of skin consists of the descendants of a single cell, which share the same inactive X chromosome — and therefore the same color — creating a coarse patchwork of red and green.

Normally, the pattern of X chromosome inactivation is not easily visualized. This color-coding technique is likely to be valuable for many studies, Nathans says, especially for research on variations caused by changes in the DNA sequence of the X chromosome, referred to as X-linked variation.  X-linked genetic variations, such as hemophilia or color blindness, are relatively common, in part because the X chromosome carries many genes — approximately 1,000, or close to 4 percent of the total.

Males who inherit an X-linked disease usually suffer its effects because they have no second X chromosome to compensate for the mutant version of the gene. Female relatives, on the other hand, are more typically “carriers” of X-linked diseases. They have the ability to pass the disease along to their male progeny, but they do not suffer from it themselves due to the normal copy of the gene on their second X chromosome.

In the tissues of certain carrier females, however, the cells that have silenced the X chromosome with a mutated gene cannot compensate for the defect in the cells that have silenced the X chromosome with the normal gene. Nathans and his team saw such a pattern when they examined the retinas of mice that were carriers for mutations in the Norrie disease gene, which is located on the X chromosome. The Norrie disease gene codes for a protein, Norrin, which controls blood vessel formation in the retina. Women who are carriers for Norrie disease can have defects in their retinas, but some women are more affected than others, and sometimes one eye is more affected than the other eye in the same individual.

The team found that in female mice that were Norrie disease carriers, variation in blood vessel structure corresponded to localized variations in X chromosome inactivation. When the X chromosome carrying the normal copy of the Norrie disease gene was silenced in a group of cells, the blood vessels nearby failed to form properly. In contrast, when the X chromosome carrying the mutated copy of the Norrie disease gene was silenced, the nearby blood vessels developed normally.

“X chromosome inactivation is a fascinating aspect of mammalian biology,” says Nathans. “This new technique for visualizing the pattern of X chromosome inactivation should be particularly useful for looking at the role that this process plays in brain development, including the ways that it contributes to differences between the left and right sides of the female brain, and to differences in brain structure between males and females and among different females, including identical twins.”

The research, published today in the journal Cell Metabolism, provides further insights on how the insulin-producing beta cells are formed in the pancreas. The team discovered that mutations in two specific genes which are important for development of the pancreas can cause the disease. These findings increase the number of known genetic causes of neonatal diabetes to 20. The study was funded by the Wellcome Trust, Diabetes UK, European Community’s Seventh Framework Programme, with some of the authors supported by the National Institute for Health Research (NIHR).

Dr Sarah Flanagan, lead author on the paper, said: “We are very proud to be able to give answers to the families involved on why their child has diabetes. Neonatal diabetes is diagnosed when a child is less than six months old, and some of these patients have added complications such as muscle weakness and learning difficulties with or without epilepsy.

“Our genetic discovery is critical to the advancement of knowledge on how insulin-producing beta cells are formed in the pancreas, which has implications for research into manipulating stem cells, which could one day lead to a cure.”

Dr Alasdair Rankin, Diabetes UK  Director of Research, said: “As well as shedding further light on the genetic causes of neonatal diabetes and providing answers for parents of children with this rare condition, this work helps us understand how the pancreas develops. Many people with diabetes can no longer make insulin and would benefit from therapies that replace the insulin producing beta cells of the pancreas. The results of this study are critical to bringing the day closer when this type of treatment is possible.”

Neonatal diabetes is caused by a change in a gene which affects insulin production. This means that levels of blood glucose (sugar) in the body rise dangerously high.

The Exeter team is the leading centre for neonatal diabetes having recruited over 1200 patients from more than 80 countries. This specific study focussed on 147 young people with neonatal diabetes, a rare condition which affects approximately 1 in 100,000 births. Following a systematic screen, 110 patients received a genetic diagnosis. For the remaining 37 patients, mutations in genes important for human pancreatic development were screened. Mutations were found in 11 patients, four of which were in one of two genes not previously known to cause neonatal diabetes (NKX2-2 and MNX1).

For many of the 121 (82%) patients who received a genetic diagnosis, knowing the cause of the diabetes will result in improved treatment, and for all the patients it will provide important information on risk of neonatal diabetes in future pregnancies. These patients also provide important scientific insights into pancreatic development.

Although drugs have been developed that inhibit the imbalance of neurotransmitters in the brain – a condition which causes many brain disorders and nervous system diseases – the exact understanding of the mechanism by which these drugs work has not yet been fully explained.

Now, researchers at the Hebrew University of Jerusalem, using baker’s yeast as a model, have deciphered the mode by which the inhibitors affect the neurological transmission process and have even been able to manipulate it.

Their work, reported in a recent article in the Journal of Biological Chemistry, raises hopes that these insights could eventually guide clinical scientists to develop new and more effective drugs for brain disorders associated with neurotransmitter imbalance.

All of the basic tasks of our existence are executed by the brain – whether it is breathing, heartbeat, memory building or physical movements – which depend on the highly regulated and efficient release of neurotransmitters – chemicals that act as messengers enabling extremely rapid connections between the neurons in the brain.

When even one part of the everyday “conversation” between neighboring neurons breaks down, the results can be devastating. Many brain disorders and nervous system diseases, including Huntington’s disease, various motor dysfunctions and even Parkinson’s disease, have been linked to problems with neurotransmitter transport.

The neurotransmitters are stored in the neuron in small, bubble-like compartments, called vesicles, containing transport proteins that are responsible for the storage of the neurotransmitters into the vesicles.

The storage of certain neurotransmitters is controlled by what is called the vesicular monoamine transporter (VMAT), which is known to transport a variety of vital neurotransmitters, such as adrenaline, dopamine and serotonin.

In addition, it can also transport the detrimental MPP+, a neurotoxin involved in models of Parkinson’s disease.

A number of studies demonstrated the significance of VMAT as a target for drug therapy in a variety of pathologic states, such as high blood pressure, hyperkinetic movement disorders and Tourette syndrome.

Many of the drugs that target VMAT act as inhibitors, including the classical VMAT2 inhibitor, tetrabenazine. Tetrabenazine has long been used for the treatment of motor dysfunctions associated with Huntington’s disease and other movement disorders. However, the mechanism by which the drug affects the storage of neurotransmitters was not fully understood.

The Hebrew University study set out, therefore, to achieve an understanding of the basic biochemical mechanism underlying the VMAT reaction, with a view towards better controlling it through new drug designs.

The research was conducted by in the laboratory of Prof. Shimon Schuldiner of the Hebrew University’s Department of Biological Chemistry; Dr.Yelena Ugolev, postdoctoral fellow in the laboratory; and research students Tali Segal, Dana Yaffe and Yael Gros.

To identify protein sequences responsible for tetrabenazine binding, the Hebrew University scientists harnessed the power of yeast genetics along with the method of directed evolution.

Expressing the human protein VMAT in baker’s yeast cells confers them with the ability to grow in the presence of toxic substrates, such as neurotoxin MPP+. Directed evolution mimics natural evolution in the laboratory and is a method used in protein engineering.

By using rounds of random mutations targeted to the gene encoding the protein of interest, the proteins can be tuned to acquire new properties or to adapt to new functions or environment.

The study led to identification of important flexible domains (or regions) in the structure of the VMAT, responsible for producing optional rearrangements in tetrabenazine binding, and also enabling regulation of the velocity of the neurotransmitter transporter.

Utilizing these new, controllable adaptations could serve as a guide for clinical scientists to develop more efficient drugs for brain disorders associated with neurotransmitter imbalance, say the Hebrew University researchers.

Although brain growth slows as individuals age, some regions of the brain continue to develop for longer than others, creating new connections and remodeling existing circuitry. How this happens is a key question in neuroscience, with implications for brain health and neurodegenerative diseases. New research published today shows that those areas of the adult brain that consume more fuel than scientists might expect also share key characteristics with the developing brain. Two Allen Brain Atlas resources – the Allen Human Brain Atlas and the BrainSpan Atlas of the Developing Human Brain – were crucial to uncovering the significance of these sugar-hungry regions. The results are published this month in the journal Cell Metabolism.

"These experiments and analysis represent the first union of its kind between functional imaging data and a biological mechanism, with the Allen Brain Atlas resources helping to bridge that gap," comments Michael Hawrylycz, Ph.D., Investigator with the Allen Institute for Brain Science and co-author of the study. Data from PET scans provides structural insight into the brain, but until now, has not been able to elucidate function. "Now we can make the comparison between the functional data and the gene expression data," says Hawrylycz, "so instead of just the ‘where,’ we now also have the ‘what’ and ‘how.’"

The brain needs to constantly metabolize fuel in order to keep running, most often in the form of glycolysis: the breaking down of stored sugar into useable energy. PET scans of the brain, which illuminate regions consuming sugar, show that some select areas of the brain seemed to exhibit fuel consumption above and beyond what was needed for basic functioning. In cancer biology, this same well-known phenomenon of consuming extra fuel—called “aerobic glycolysis”—is thought to provide support pathways for cell proliferation. In the brain, aerobic glycolysis is dramatically increased during childhood and accounts for as much as one third of total brain glucose consumption at its peak around 5 years of age, which is also the peak of synapse development.

Since aerobic glycolysis varies by region of the brain, Hawrylycz and co-author Marcus Raichle, Ph.D., at Washington University in St. Louis, wondered whether regions of the brain with higher levels of aerobic glycolysis might be associated with equivalent growth processes, like synapse formation. If so, this would point to aerobic glycolysis as a reflection of “neoteny,” or persistent brain development like the kind that takes place during early childhood.

In order to delve into the significance of aerobic glycolysis, researchers examined the genes expressed at high levels in those regions where aerobic glycolysis was taking place. The team identified 16 regions of the brain with elevated levels of aerobic glycolysis and ranked their neotenous characteristics. True to prediction, they found that gene expression data from those 16 regions suggested highly neotenous behavior.

The next phase was to identify which genes were specifically correlated with aerobic glycolysis in those regions. The Allen Brain Atlas resources proved crucial in this task, helping to pinpoint gene expression in different regions at various points in development. The Allen Human Brain Atlas was used to investigate the adult human brain, while the BrainSpan Atlas of the Developing Human Brain, developed by a consortium of partners and funded by the National Institutes of Health, provided a window into how gene expression changes as the brain ages.

Analysis of the roles of those genes pointed clearly towards their roles in growth and development; top genes included those responsible for axon guidance, potassium ion channel development, synaptic transmission and plasticity, and many more. The consistent theme was development, pointing to aerobic glycolysis as a hallmark for neotenous, continually developing regions of the brain.

"Using both the adult and developmental data, we were able to study gene expression at each point in time," describes Hawrylycz. "From there, we were able to see the roles of those genes that were highly expressed in regions with aerobic glycolysis. As it turns out, those genes are consistently involved in the remodeling and maturation process, synaptic growth and neurogenesis—all factors in neoteny." "The regions we identified as being neotenous are areas of the cortex particularly associated with development of intelligence and learning," explains Hawrylycz. "Our results suggest that aerobic glycolysis, or extra fuel consumption, is a marker for regions of the brain that continue to grow and develop in similar ways to the early human brain."

Australian researchers have shed more light on an underexplored aspect of the important brain-signaling system that controls appetite, body composition and energy use. Their findings suggest that a specific gene regulating our body clock may play a central role in determining how fat we become.

Evolution has preserved the ‘neuropeptide Y (NPY) system’, as it is known, in most species – indicating its importance – and much of our understanding comes from studying it in mice. There is one important difference, however, between the NPY system in mouse and man.

In man, the neurotransmitter NPY communicates with four well-known ‘cell surface receptors’ in the brain (Y1, Y2, Y4 and Y5), which in turn trigger the system’s effects.

The new study has shown that mice have an additional receptor, Y6, which has profound effects on their body composition. Y6 is produced in a very small region of the brain that regulates the body clock, as well as growth hormone production.

PhD student Ernie Yulyaningsih, Dr Kim Loh, Dr Shu Lin and Professor Herbert Herzog from Sydney’s Garvan Institute of Medical Research, together with Associate Professor Amanda Sainsbury-Salis, now at the University of Sydney, deleted the Y6 gene from mice to understand its effects. Their study showed that mice without the Y6 gene were smaller, and had less lean tissue, than normal mice. On the other hand, as they aged, these ‘knockout mice’ grew fatter than the normal mice, especially when fed a high-fat diet. In that case, they became obese and developed metabolic problems similar to diabetes. These findings are now published online in the prestigious international journal, Cell Metabolism.

While the gene encoding the Y6 receptor is altered in man, Professor Herzog believes it would be unwise to ignore it because the development of anti-obesity drugs relies heavily on mouse studies.

“It is now clear to us that signaling through the Y6 receptor system is critical for the ways in which energy is used at different times of the day,” said Professor Herbert Herzog.

“Our work shows that Pancreatic Polypeptide has a very high affinity for Y6 in mice. It’s a satiety signal, and probably controls the circadian aspect of food intake – because the same amount of calories eaten at different times of the day has different effects on body weight.”

“The Y6 gene is highly expressed in a part of the brain called the ‘hypothalamic suprachiasmatic nucleus’, which is known to control the body’s circadian rhythm and may also critically modulate metabolic processes in response to food. The gene stimulates higher levels of certain peptides, including vasoactive intestinal peptide (VIP) – which controls growth hormone release.”

“While it is not clear whether the Y6 receptor is fully active in humans, Pancreatic Polypeptide is highly expressed – even more so than in mice – and it’s possible that another receptor to which the peptide has high affinity, such as Y4, could have taken over this function.”

Associate Professor Amanda Sainsbury-Salis expressed surprise at the impact of the Y6 gene deletion on mice, commenting “I find it amazing that one gene, which is expressed in the small part of the brain that controls the body clock, has such a profound impact on how much fat is stored on the body, and how much lean tissue is maintained.”

“Importantly, we use mice as models of human beings in research, and so when looking for anti-obesity drugs, we need to fully understand the function of the NPY system in this animal model to understand how similar circuits in humans connect with the body clock.”

An experimental treatment for Parkinson’s disease reduced by nearly two hours on average the period each day when medication failed to control patients’ slowness and shaking, according to results from a double-blind, phase III clinical trial published in December 2013, in Lancet Neurology. 

The study compared AbbVie’s levodopa-carbidopa intestinal gel against the same medication in pill form in patients with advanced disease. 

The University of Alabama at Birmingham was among the sites for the study, with David G. Standaert, M.D., Ph.D., chair of the UAB Department of Neurology, an author. Led by the Mount Sinai School of Medicine, preliminary results from the study were first presented at the annual meeting of the American Academy of Neurology in April 2012. 

Parkinson’s disease results from the loss of brain cells that make dopamine, which helps to control movement. As dopamine levels fall, patients experience tremors, muscle stiffness and loss of balance. A commonly prescribed treatment, the levodopa-carbidopa combination works as the body converts levodopa into dopamine and carbidopa escorts levodopa to the right part of the brain. The problem is that patients face hours of uncontrolled slowness, freezing and tremors each day — called “off-time” — as the treatment gets into place or wears off.

One reason for the break in treatment coverage is that it comes in a pill, and pills sit in the stomach for up to six hours waiting for it to empty into the small intestine. It is only there that levodopa encounters the proteins capable of transporting it into the bloodstream en route to the brain. Thus, researchers envisioned a system that steadily delivers levodopa gel directly into the small intestine through a surgically placed tube, and with the help of a pump worn on the belt.

“The results are very exciting, considering that other recently approved drugs on the market reduce off-time by, at most, just over an hour,” said Standaert. “In the study, the gel treatment helped patients who had run out of alternatives with current medications. We believe it may be an important new option for patients with severe Parkinson’s, with benefits comparable to more invasive techniques like deep brain stimulation.”

Patients using the gel system saw an average reduction in daily off-time of 1.91 hours, and an increase in “on-time” without troublesome dyskinesia of 1.86 hours compared with the pill form. Nearly all subjects experienced at least one side effect, although most were short-lived and moderate.

QBI scientists at The University of Queensland have found that honeybees use the pattern of polarised light in the sky invisible to humans to direct one another to a honey source.

The study, conducted in Professor Mandyam Srinivasan’s laboratory at the Queensland Brain Institute, a member of the Australian Research Council Centre of Excellence in Vision Science (ACEVS), demonstrated that bees navigate to and from honey sources by reading the pattern of polarised light in the sky.

“The bees tell each other where the nectar is by converting their polarised ‘light map’ into dance movements,” Professor Srinivasan said.

“The more we find out how honeybees make their way around the landscape, the more awed we feel at the elegant way they solve very complicated problems of navigation that would floor most people – and then communicate them to other bees,” he said.

The discovery shines new light on the astonishing navigational and communication skills of an insect with a brain the size of a pinhead.

The researchers allowed bees to fly down a tunnel to a sugar source, shining only polarised light from above, either aligned with the tunnel or at right angles to the tunnel.

They then filmed what the bees ‘told’ their peers, by waggling their bodies when they got back to the hive.

“It is well known that bees steer by the sun, adjusting their compass as it moves across the sky, and then convert that information into instructions for other bees by waggling their body to signal the direction of the honey,” Professor Srinivasan said.

“Other laboratories have shown from studying their eyes that bees can see a pattern of polarised light in the sky even when the sun isn’t shining: the big question was could they translate the navigational information it provides into their waggle dance.”

The researchers conclude that even when the sun is not shining, bees can tell one another where to find food by reading and dancing to their polarised sky map.

In addition to revealing how bees perform their remarkable tasks, Professor Srinivasan says it also adds to our understanding of some of the most basic machinery of the brain itself.

Professor Srinivasan’s team conjectures that flight under polarised illumination activates discrete populations of cells in the insect’s brain.

When the polarised light was aligned with the tunnel, one pair of ‘place cells’ – neurons important for spatial navigation – became activated, whereas when the light was oriented across the tunnel a different pair of place cells was activated.

The researchers suggest that depending on which set of cells is activated, the bee can work out if the food source lies in a direction toward or opposite the direction of the sun, or in a direction ninety degrees to the left or right of it.

Children are likely to have stronger muscles if their mothers had a higher level of vitamin D in their body during pregnancy, according to new research from the Medical Research Council Lifecourse Epidemiology Unit (MRC LEU) at the University of Southampton.

Low vitamin D status has been linked to reduced muscle strength in adults and children, but little is known about how variation in a mother’s status during pregnancy affects her child.

Low vitamin D concentrations are common among young women in the UK, and although women are recommended to take an additional 10μg/day of vitamin D in pregnancy, supplementation is often not taken up.

In the research, published in the January edition of the Journal of Clinical Endocrinology and Metabolism, vitamin D levels were measured in 678 mothers in the later stages of pregnancy.

When the children were four years old, grip strength and muscle mass were measured. Results showed that the higher the levels of vitamin D in the mother, the higher the grip strength of the child, with an additional, but less pronounced association between mother’s vitamin D and child’s muscle mass.

Lead researcher Dr Nicholas Harvey, Senior Lecturer at the MRC LEU at the University of Southampton, comments: “These associations between maternal vitamin D and offspring muscle strength may well have consequences for later health; muscle strength peaks in young adulthood before declining in older age and low grip strength in adulthood has been associated with poor health outcomes including diabetes, falls and fractures. It is likely that the greater muscle strength observed at four years of age in children born to mothers with higher vitamin D levels will track into adulthood, and so potentially help to reduce the burden of illness associated with loss of muscle mass in old age.”

The 678 women who took part in the study are part of the Southampton Women’s Survey, one of the largest and best characterised such studies globally.

Professor Cyrus Cooper, Professor of Rheumatology and Director of the MRC LEU at the University of Southampton, who oversaw this work, added: “This study forms part of a larger programme of research at the MRC Lifecourse Epidemiology Unit and University of Southampton in which we are seeking to understand how factors such as diet and lifestyle in the mother during pregnancy influence a child’s body composition and bone development. This work should help us to design interventions aimed at optimising body composition in childhood and later adulthood and thus improve the health of future generations.”

Researchers from the University of Illinois at Chicago College of Medicine have found that dysfunction in a single gene in mice causes fasting hyperglycemia, one of the major symptoms of type 2 diabetes. Their findings were reported online in the journal Diabetes.

If a gene called MADD is not functioning properly, insulin is not released into the bloodstream to regulate blood sugar levels, says Bellur S. Prabhakar, professor and head of microbiology and immunology at UIC and lead author of the paper.

Type 2 diabetes affects roughly 8 percent of Americans and more than 366 million people worldwide. It can cause serious complications, including cardiovascular disease, kidney failure, loss of limbs and blindness.

In a healthy person, beta cells in the pancreas secrete the hormone insulin in response to increases in blood glucose after eating. Insulin allows glucose to enter cells where it can be used as energy, keeping glucose levels in the blood within a narrow range. People with type 2 diabetes don’t produce enough insulin or are resistant to its effects. They must closely monitor their blood glucose throughout the day and, when medication fails, inject insulin.

In previous work, Prabhakar isolated several genes from human beta cells, including MADD, which is also involved in certain cancers. Small genetic variations found among thousands of human subjects revealed that a mutation in MADD was strongly associated with type 2 diabetes in Europeans and Han Chinese.

People with this mutation had high blood glucose and problems of insulin secretion – the “hallmarks of type 2 diabetes,” Prabhakar said. But it was unclear how the mutation was causing the symptoms, or whether it caused them on its own or in concert with other genes associated with type 2 diabetes.

To study the role of MADD in diabetes, Prabhakar and his colleagues developed a mouse model in which the MADD gene was deleted from the insulin-producing beta cells. All such mice had elevated blood glucose levels, which the researchers found was due to insufficient release of insulin.

“We didn’t see any insulin resistance in their cells, but it was clear that the beta cells were not functioning properly,” Prabhakar said. Examination of the beta cells revealed that they were packed with insulin. “The cells were producing plenty of insulin, they just weren’t secreting it,” he said.

The finding shows that type 2 diabetes can be directly caused by the loss of a properly functioning MADD gene alone, Prabhakar said. “Without the gene, insulin can’t leave the beta cells, and blood glucose levels are chronically high.”

Prabhakar now hopes to investigate the effect of a drug that allows for the secretion of insulin in MADD-deficient beta cells.

“If this drug works to reverse the deficits associated with a defective MADD gene in the beta cells of our model mice, it may have potential for treating people with this mutation who have an insulin-secretion defect and/or type 2 diabetes,” he said.

In the journal Neurology, researchers report a novel technique that enables a patient with “word blindness” to read again.

Word blindness is a rare neurological condition. (The medical term is “alexia without agraphia.”) Although a patient can write and understand the spoken word, the patient is unable to read.

The article is written by Jason Cuomo, Murray Flaster, MD, PhD and Jose Biller, MD, of Loyola University Medical Center.

Here’s how the technique works: When shown a word, the patient looks at the first letter. Although she clearly sees it, she cannot recognize it. So beginning with the letter A, she traces each letter of the alphabet over the unknown letter until she gets a match. For example, when shown the word Mother, she will trace the letters of the alphabet, one at a time, until she comes to M and finds a match. Three letters later, she guesses correctly that the word is Mother.

"To see this curious adaption in practice is to witness the very unique and focal nature" of the deficit, the authors write.

The authors describe how word blindness came on suddenly to a 40-year-old kindergarten teacher and reading specialist. She couldn’t make sense of her lesson plan, and her attendance sheet was as incomprehensible as hieroglyphs. She also couldn’t tell time.

The condition was due to a stroke that probably was caused by an unusual type of blood vessel inflammation within the brain called primary central nervous system angiitis.

Once a passionate reader, she was determined to learn how to read again. But none of the techniques that she had taught her students – phonics, sight words, flash cards, writing exercises, etc. – worked. So she taught herself a remarkable new technique that employed tactile skills that she still possessed.

The woman can have an emotional reaction to a word, even if she can’t read it. Shown the word “dessert,” she says “Oooh, I like that.” But when shown “asparagus,” she says, “Something’s upsetting me about this word.”

Shown two personal letters that came in the mail, she correctly determined which was sent by a friend of her mother’s and which was sent by one of her own friends. “When asked who these friends were, she could not say, but their names nevertheless provoked an emotional response that served as a powerful contextual clue,” the authors write.

What she most misses is reading books to children. She teared up as she told the authors: “One day my mom was with the kids in the family, and they were all curled up next to each other, and they were reading. And I started to cry, because that was something I couldn’t do.”