Researchers reveal geometric grid structure of the brain
The brain appears to be wired more like the checkerboard streets of New York City than the curvy lanes of Columbia suggests a new brain imaging study. The most detailed images to date reveal a pervasive 3D grid structure with no diagonals, say scientists funded by the US National Institutes of Health, who reported that, “far from being just a tangle of wires, the brain’s connections turn out to be more like ribbon cables – folding 2D sheets of parallel neuronal fibres that cross paths at right angles, like the warp and weft of a fabric.” They continued: “This grid structure is continuous and consistent at all scales and across humans and other primate species.”
Van Wedeen of Massachusetts General Hospital (MGH), the A.A. Martinos Center for Biomedical Imaging and the Harvard Medical School worked on the report, which was published in Science and funded in part, by the NIH’ s National Institute of Mental Health (NIMH), the Human Connectome Project and other NIH components.
NIMH Director Thomas R. Insel, said: “Getting a high resolution wiring diagram of our brains is a landmark in human neuroanatomy. This new technology may reveal individual differences in brain connections that could aid diagnosis and treatment of brain disorders.”
Knowledge gained from the study helped shape design specifications for the most powerful brain scanner of its kind, which was installed at MGH’ s Martinos Center last fall. The new diffusion magnetic resonance imaging (MRI) scanner can visualise the networks of crisscrossing fibres, through which different parts of the brain communicate with each other, in 10-fold higher detail than conventional scanners, said Wedeen.
“This one-of-a-kind instrument is bringing into sharper focus an astonishingly simple architecture that makes sense in light of how the brain grows,” he explained. “The wiring of the mature brain appears to mirror three primal pathways established in embryonic development.”
As the brain gets wired up in early development, its connections form along perpendicular pathways, running horizontally, vertically and transversely. This grid structure appears to guide connectivity like lane markers on a highway, which would limit options for growing nerve fibres to change direction during development. If they can turn in just four directions: left, right, up or down, this may enforce a more efficient, orderly way for the fibres to find their proper connections and for the structure to adapt through evolution, suggest the researchers.
Obtaining detailed images of these pathways in human brain has long eluded researchers, in part, because the human cortex, or outer mantle, develops many folds, nooks and crannies that obscure the structure of its connections. In diffusion imaging, the scanner detects movement of water inside the fibres to reveal their locations. A high resolution technique called diffusion spectrum imaging (DSI) makes it possible to see the different orientations of multiple fibres that cross at a single location, which is the key to seeing the grid structure.
Among immediate implications, the findings suggest a simplifying framework for understanding the brain’s structure, pathways and connectivity. The technology used in the current study was able to see only about 25% of the grid structure in human brain. It was only apparent in large central circuitry, not in outlying areas where the folding obscures it. But lessons learned were incorporated into the design of the newly installed Connectom scanner, which can see 75% of it, according to Wedeen.
Much as a telescope with a larger mirror or lens provides a clearer image, the new scanner markedly boosts resolving power by magnifying magnetic fields with magnetically stronger copper coils, called gradients. Gradients make it possible to vary the magnetic field and get a precise fix on locations in the brain. The Connectom scanner’ s gradients are seven times stronger than those of conventional scanners. Scans that would have previously taken hours, and would therefore have been impractical with living human subjects, can now be performed in minutes.
Reference: Wedeen VJ, et al. The Geometric Structure of the Brain Fiber Pathways: A Continuous Orthogonal Grid. March 30, 2012, Science.
Smaller breaths better for sick lungs
Carefully adjusting mechanical ventilator settings in the intensive care unit to pump smaller breaths into very sick lungs can reduce the chances of dying by as much as 8%, according to a study by critical care experts at Johns Hopkins. Study participants were evaluated for two years after their acute lung injury.
“Adjusting the ventilator to keep the breath size and lung pressures lower can have a dramatic effect on whether or not a patient dies from their lung injury, even long after they leave the ICU,” said lead study investigator and critical care specialist Dale Needham. “People with acute lung injury are very sick and often in the hospital for weeks, not days.”
The Johns Hopkins team’ s latest findings, published in the British Medical Journal, come from evaluating the ventilator settings and subsequent survival, or death, of 485 men and women, most over 50, spending at least a week or more in intensive care. All had life-threatening acute lung injury. In what is the most comprehensive study evaluating the long-term effects of mechanical ventilation on acute lung injury patients, researchers found that over the entire ICU stay, on average, for every one unit increase in the ventilator setting – known as tidal volume, calculated in millilitres per kilogram of body weight – there was a commensurate 18% jump in the risk of mortality over two years, a finding which Needham says, “represents a huge difference” and reinforces the message to critical care specialists to keep tidal volumes and lung pressures adherent to known lungprotective ventilator settings.
Previous research had shown that using lung-protective ventilator settings reduced inflammation and decreased the amount of time that other vital organs, such as the heart and kidneys, were not functioning normally. Short-term survival rates also improved.
Needham says that in people with acute lung injury, including acute respiratory distress syndrome, larger breath sizes put more stress on the lungs because only a small portion of healthy tissue is available to service the body’ s oxygen needs.
“Our study shows there is still a lot of room for improvement in how we treat acute lung injury in the ICU,” says Needham, who points out that one of the biggest barriers to fixing the problem is a lack of understanding of the best methods for having ICU staff quickly recognize acute lung injury and change their traditional practice to adopt lungprotective ventilation.
Another barrier is miscalculating the correct tidal volume setting, as the formula is based on predicted body weight instead of actual body weight. Estimates show that as many as two-thirds of ICU patients are overweight, which has no bearing on physical lung size. People who are the same height and gender will have similarly sized lungs, even if one weighs significantly more than the other.
“Such details can have lasting effects,” says Needham. “Critical care practitioners have to refocus our efforts on not simply getting patients out of the ICU alive, but on changing traditional medical care in the ICU to improve patients’ recovery over the longer term.”
Experts say the chances of dying from acute lung injury (ALI), as caused by pneumonia, aspirating food or drink into the lungs, major trauma or near drowning, are already high, due to the resulting widespread inflammation and destruction of lung tissue. Of the estimated 190,000 Americans who suffer from ALI each year, more than 74,000 – almost 40% – will die in hospital, and 60% are likely to die within two years of their respiratory event.
Low iron levels in blood give clue to blood clot risk
People with low levels of iron in the blood have a higher risk of dangerous blood clots, according to research published in the journal Thora. A study of clotting risk factors in patients with an inherited blood vessel disease suggests that treating iron deficiency might be important for preventing potentially lethal blood clots. Each year, one in every 1,000 people in the UK is affected by deep vein thrombosis – blood clots that form in the veins. These can cause pain and swelling, but can also be fatal if the clot is dislodged and travels into the blood vessels of the lungs. Although some risk factors for blood clots are recognised, such as major surgery, immobility and cancer, often there is no clear reason for the blood clot.
To look for new risk factors for blood clots, scientists at Imperial College London studied patients with hereditary haemorrhagic telangiectasia (HHT). HHT is an inherited disease of the blood vessels, the main symptoms of which are excessive bleeding from the nose and gut. Previous research by the same group had found that HHT patients have a higher risk of blood clots, but the reason for this was unclear.
“Most of our patients who had blood clots did not have any of the known risk factors ,” said the paper’ s lead author Dr Claire Shovlin from the National Heart and Lung Institute at Imperial College London and an honorary consultant at Imperial College Healthcare NHS Trust. “We thought that studying people with HHT might tell us something important about the wider population.”
Dr Shovlin and her team analysed blood from 609 patients to look for differences between the patients who had blood clots and those who did not. Many of the patients had low iron levels because of iron lost through bleeding. The researchers found that low levels of iron in the blood were a strong risk factor for blood clots. Patients who took iron supplements did not have higher risk, suggesting that treatment for iron deficiency can prevent blood clots.
Iron deficiency anaemia is thought to affect at least 1 billion people worldwide. The association with blood clot risk might not have been found before because the iron levels demonstrating the link fluctuate during the day, and other markers of iron deficiency can be spuriously high if other medical conditions are present. Consistent timing of blood samples, as in this study, is therefore important for establishing correlations with health outcomes.
The link between iron levels and blood clots appears to be dependent on factor VIII – a blood protein which promotes normal clotting. High levels of factor VIII in the blood are also a strong risk factor for blood clots, and low iron levels were strongly associated with higher levels of factor VIII. The gene encoding factor VIII has sites where iron-binding proteins can bind, making it plausible that iron levels could regulate the factor VIII gene, and that this might be the mechanism for the link. “We can speculate that in evolutionary terms, it might be advantageous to promote blood clotting when your blood is low in iron, in order to prevent further blood loss,” Dr Shovlin said.
Memory study shines light on future treatments for Alzheimer’s
As a result of studying tiny bits of genetic material that control protein formation in the brain, Johns Hopkins scientists say they have new clues to how memories are made and how drugs might someday be used to stop disruptions in the process that lead to mental illness and brain wasting diseases.
In a report published in Cell, the researchers said certain microRNAs – genetic elements that control which proteins get made in cells – are the key to controlling the actions of so-called brain-derived neurotrophic factor (BDNF), long linked to brain cell survival, normal learning and memory boosting.
During the learning process, cells in the brain’ s hippocampus release BDNF, a growth-factor protein that ramps up production of other proteins involved in establishing memories. Yet, by mechanisms that were never understood, BDNF is known to increase production of less than 4% of the different proteins in a brain cell.
Mollie Meffert, Associate Professor of Biological Chemistry and Neuroscience at the Johns Hopkins University School of Medicine, set out to try and track down how BDNF determines which proteins to turn on, and to uncover the role of regulatory microRNAs. MicroRNAs are small molecules that bind to and block messages that act as protein blueprints from being translated into proteins. Many microRNAs in a cell shut down protein production, and, conversely, the loss of certain microRNAs can cause higher production of specific proteins.
The researchers measured microRNA levels in brain cells treated with BDNF and compared them to microRNA levels in neurons not treated with BDNF. Their findings suggest that BNDF treatment also can halt the production of certain proteins and decrease production of certain proteins. Says Meffert, some of these proteins may need to be decreased during learning and memory, whereas others may not contribute to the process at all.
They also found that messages that aren’t translated into proteins can accumulate inside small formations within cells. Using a microscope, the researchers watched a lab dish containing brain cells that had been marked with a fluorescent molecule that labels these formations as glowing spots. Treating cells with BDNF caused the number and size of the glowing spots to increase. The researchers determined that BDNF uses microRNA to send messages to these spots where they can be exiled away from the translating machinery that turns them into protein.
Meffert said: “Monitoring these fluorescent complexes gave us a window that we needed to understand how BDNF is able to target the production of only certain proteins that help neurons to grow and make learning possible. Now that we know how BDNF boosts production of learning and memory proteins, we have an opportunity to explore whether therapeutics can be designed to enhance this mechanism for treatment of patients with mental disorders and neurodegenerative diseases like Alzheimer’s disease.”
Reference: Yu-Wen A. Huang, Claudia R. Ruiz, E.C.H. Eyler, Kathie Lin, and Mollie K. Meffert (2012), Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis. Cell, 148(5); 933-946. PMID: 22385959. 10.1016/j.cell.2012.01.036
Heart failure’s effects in cells can be reversed with a rest
Structural changes in heart muscle cells after heart failure can be reversed by allowing the heart to rest, according to research at Imperial College London. Findings from a study in rats published in the European Journal of Heart Failure show that the condition’ s effects on heart muscle cells are not permanent, as has generally been thought. The discovery could open the door to new treatment strategies.
Patients with advanced heart failure are sometimes fitted with a left ventricle assist device (LVAD). The LVAD is a small pump that boosts the function of the heart and reduces strain on the left ventricle, the biggest chamber of the heart, which pumps blood around the body’s main circulation.
In 2006, researchers at Imperial led by Professor Magdi Yacoub showed that resting the heart using an LVAD fitted for a limited time can help the heart muscle to recover. The new study is a major step in understanding the mechanisms for this improvement at the level of heart muscle cells.
The Imperial researchers studied the changes that occur in heart muscle cells during heart failure in rats, and whether “unloading” the heart can reverse these changes.
Dr Cesare Terracciano, from the National Heart and Lung Institute (NHLI) at Imperial, who supervised the study, said: “If you injure a muscle in your leg, you rest it and this allows it to recover. The heart can’t afford to rest – it has to keep beating continuously. LVADs reduce the load on the heart while maintaining the supply of blood to the body, and this seems to help the heart recover. We wanted to see what unloading does to heart muscle cells, to see how this works.”
To study the effect of unloading, they transplanted a failing heart from one rat into another rat alongside that rat’ s healthy heart, so that it received blood but did not have to pump. After the heart was able to rest, several changes in the structure of heart muscle cells that impair how well they can contract were reversed.
“This is the first demonstration that this important form of remodelling of heart muscle cells induced by heart failure is reversible,” said Michael Ibrahim, also from the NHLI at Imperial. “If we can discover the molecular mechanisms for these changes, it might be possible to induce recovery without a serious procedure like having an LVAD implanted.” doi: 10.1093/eurjhf/hfs038
Scientists find an answer to how brain cells remember memories
Researchers at the RIKEN-MIT Center for Neural Circuit Genetics have discovered an answer to the long-standing mystery of how brain cells can both remember new memories while also maintaining older ones.
They found that specific neurons in a brain region called the dentate gyrus serve distinct roles in memory formation depending on whether the neural stem cells that produced them were of old versus young age.
The study appeared in the March 30 issue of Cell and links the cellular basis of memory formation to the birth of new neurons – a finding that could unlock a new class of drug targets to treat memory disorders.
The findings also suggest that an imbalance between young and old neurons in the brain could disrupt normal memory formation during post-traumatic stress disorder (PTSD) and aging. “In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging,” said the study’s senior author Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center.
Other authors include Toshiaki Nakashiba and researchers from the RIKEN-MIT Center and Picower Institute at MIT; the laboratory of Michael S. Fanselow at the University of California at Los Angeles; and the laboratory of Chris J. McBain at the US National Institute of Child Health and Human Development.
In the study, the authors tested mice in two types of memory processes. Pattern separation is the process by which the brain distinguishes differences between similar events, like remembering two Madeleine cookies with different tastes. In contrast, pattern completion is used to recall detailed content of memories based on limited clues, like recalling who one was with when remembering the taste of the Madeleine cookies.
Pattern separation forms distinct new memories based on differences between experiences; pattern completion retrieves memories by detecting similarities. Individuals with brain injury or trauma may be unable to recall people they see every day. Others with PTSD are unable to forget terrible events. “Impaired pattern separation due to the loss of young neurons may shift the balance in favour of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients,” Tonegawa said.
Neuroscientists have long thought these two opposing and potentially competing processes occur in different neural circuits. The dentate gyrus, a structure with remarkable plasticity within the nervous system and its role in conditions from depression to epilepsy to traumatic brain injury – was thought to be engaged in pattern separation and the CA3 region in pattern completion. Instead, the MIT researchers found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.
The MIT researchers assessed pattern separation in mice who learned to distinguish between two similar but distinct chambers: one safe and the other associated with an unpleasant foot shock. To test their pattern completion abilities, the mice were given limited cues to escape a maze they had previously learned to negotiate. Normal mice were compared with mice lacking either young neurons or old neurons. The mice exhibited defects in pattern completion or separation depending on which set of neurons was removed.
“By studying mice genetically modified to block neuronal communication from old neurons – or by wiping out their adultborn young neurons – we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it,” co-author Toshiaki Nakashiba said. “Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons.”
The work was supported by the RIKENMIT Center for Neural Circuit Genetics, Howard Hughes Medical Institute, Otsuka Maryland Research Institute, Picower Foundation and the National Institutes of Health.
Reference: Toshiaki Nakashiba, et al. “Young Dentate Granule Cells Mediate Pattern Separation whereas Old Granule Cells Facilitate Pattern Completion.” Cell - 30 March 2012 (Vol. 149, Issue 1, pp. 188-201)
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