Posts tagged neuroscience
Articles and news from the latest research reports.
Diabetes drug shows promise in treatment of neurodegenerative disease
Researchers in Spain have found that a drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. They believe that their findings may be relevant to other neurodegenerative diseases. A Phase II trial will be starting shortly. The research is published simultaneously on line in the journal Brain.
A drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. This is an important step along the road to the development of a therapy for the human disease for which current treatment options are scarce and only partially effective, the annual conference of the European Society of Human Genetics will hear tomorrow (Sunday).
Professor Aurora Pujol, a research professor for the Catalan Government Research Body ICREA, working as Director of the Neurometabolic Diseases Laboratory at IDIBELL, Barcelona, Spain, investigated the role of mitochondria, the power plant of the cell, in adrenoleukodystrophy, a disease caused by the inactivation of the ABCD1 transporter of fatty acids in peroxisomes. This inactivation leads to the accumulation of fatty acids in organs and blood plasma, and causes spinal cord degeneration.
“ABCD1 is a protein located in the peroxisomes, compartments of the cell that detoxify chemicals and lipids, and thus the implication of mitochondria in such a disease was not obvious. But we knew from recent research that oxidative stress – where there is increased production of chemically active oxygen-containing molecules, and also significant decrease in the effectiveness of the body’s antioxidant defences – was involved. We also knew that bioenergetic failure appeared before disease symptoms. We therefore decided to investigate the role of the mitochondria”, Professor Pujol will say.
The group of diseases known as leukodystrophies are characterised by progressive loss of the myelin sheath, the fatty covering that acts as an insulator around nerve fibres. Damage to the myelin sheath impairs the conduction of signals in the affected nerves and leads to locomotor problems.
“We knew that early oxidative damage and bioenergetic dysfunction underlay the late onset degeneration of nerve fibres observed in the mouse model of X-linked adrenoleukodystrophy (X-ALD), the most frequently inherited leukodystrophy, so we looked at mitochondria for further clues. We found that the X-ALD mice showed a loss of mitochondria at 12 months of age, prior to disease symptoms, so this could not be a consequence of the disease, but rather a contributing factor. We also knew that the pathway involved in the mitochondrial loss could be treated by the use of the diabetes drug pioglitazone, so we decided to test its effect in the mice”, Professor Pujol will say.
Pioglitazone halted the nerve fibre degeneration by preventing the loss of mitochondria, and inhibiting metabolic failure and oxidative stress in the treated mice, and hence also halted locomotor disabilities. The researchers were able to prove this both through analysis of spinal cords post mortem, and in vivo by putting the mice through a number of physical tests.
Although X-ALD is a relatively rare disease with a minimum incidence of 1 in 17 000 males, there are other neurodegenerative disorders caused by myelin sheath degeneration, for example multiple sclerosis, and many others where impaired bioenergetics combined with oxidative stress and degeneration of axons are known to be involved. The latter category of disease includes Parkinson’s, Huntington’s, and Alzheimer’s. “It is possible that our findings may be relevant to these conditions as well,” says Professor Pujol.
“Following on from these promising results, together with Professor Patrick Aubourg from the Hôpital Bicêtre, Paris, we will shortly be starting a multi-centre phase II clinical trial of pioglitazone in adult patients suffering from a late onset variant of adrenoleukodystrophy. Our research has shown that it will be feasible to monitor the biological effects of the drug by looking for biomarkers of oxidative damage in blood cells or plasma. We are happy to have made a contribution to finding a simple and effective treatment to a group of devastating diseases”, she will conclude.
(Source: alphagalileo.org)
Over-produced autism gene alters synapses, affects learning and behavior in mice
A gene linked to autism spectrum disorders that was manipulated in two lines of transgenic mice produced mature adults with irreversible deficits affecting either learning or social interaction.
The findings, published in the May 29 issue of the Journal of Neuroscience, have implications for potential gene therapies but they also suggest that there may be narrow windows of opportunity to be effective, says principal investigator Philip Washbourne, a professor of biology and member of the University of Oregon’s Institute of Neuroscience.
The research, reported by an 11-member team from three universities, targeted the impacts of alterations in the gene neuroligin 1 — one of many genes implicated in human autism spectrum disorders — to neuronal synapses in the altered mice during postnatal development and as they entered adulthood. One group over-expressed the normal gene, the other a mutated version.
Mice with higher-than-normal levels of the normal gene after a month had skewed synapses at maturity. Many were larger, appearing more mature, than normal. In these mice, Washbourne said, there were clear cognitive problems. “Behavior was just not normal. They didn’t learn very well, and they were slower to learn, but their social behavior was not impacted.”
Mice over-producing a mutated version of the gene reached adulthood with structurally immature synapses. “They were held back in development and behavior — the way they behave in terms of learning and memory, in terms of social interaction,” he said. “These were adult mice, three months old, but they behaved like normal mice at four weeks old. We saw arrested development. Learning is a little bit better, they are more flexible just like young mice, they learn faster, but their social interaction is off. To us, this looked more like Asperger’s syndrome.
"So with the same gene, doing two different manipulations — overexpressing the normal form or overexpressing a mutated form — we’ve gone to two different ends of the autism spectrum," said Washbourne, whose lab focuses on basic synapse formation and what goes wrong in relationship to autism. Work has been done in both mice and zebra fish.
"We made these mice so that we can turn the genes on and off as we want," Washbourne said. "Using an antibiotic, doxycycline, it turns off these altered genes that we inserted into their chromosomes. While on doxycycline, the mice are absolutely normal.”
However, if the inserted gene was turned off after the completion of development, mice still showed altered synapses and behavior. This result suggests that any kind of gene therapy may have to be applied to individuals with autism early on.
Effects seen in the social behavior of mice with the mutated gene, he said, are not unlike observations reported by parents of many autistic children. While normal mice prefer to engage with new mice entering their world rather than familiar others, or even a new inanimate object, these mice split their time equally. “It’s not a deficit in memory regarding which mouse is which, it’s more a weighting of their interaction. Does that mean they are autistic? I don’t know, but if you talk to parents of autistic children, one of the frustrating things they report is that their children treat complete strangers in exactly the same way that they treat them.”
While the findings provide new insights, Washbourne said, any translation into treatment could be decades away. “A problem with autism is there are many different genes potentially involved. It could be that some day, if you are diagnosed with autism, a mouth swab might allow for the identification of the exact gene that is mutated and allow for targeted therapy,” he said. “Genome sequencing already has turned up subtle mutations in lots of genes. Autism might be like cancer, with hundreds of potential combinations of faulty genes.”
(Source: uonews.uoregon.edu)
The protein profile of restless leg syndrome
A protein profile of people with restless leg syndrome (RLS), identifies factors behind disrupted sleep, cardiovascular dysfunction and pain finds research in BioMed Central’s open access journal Fluids and Barriers of the CNS. The research gives insights into the disorder, and could be useful in the development of new treatments.
It is not completely clear what causes RLS, also known as Willis Ekbom disease (WED), but in some people it is associated with iron deficiency in the brain, kidney failure, or low levels of the ‘pleasure’ neurotransmitter dopamine. It can also occur during pregnancy. It affects between 5 and 10% of the population and symptoms, which can range in severity, including sleep deprivation and decreased ability to work can lead to a reduction in quality of life. It is also a risk factor for cardiovascular disease.
Comparing the cerebral spinal fluid (CSF) of women with and without RLS, researchers from the US and Korea discovered there was a significantly altered level of six specific proteins with RLS. Dr Stephanie Patton from Penn State University who led this study explained, “Our results reveal a protein profile in the RLS/WED CSF that is consistent with iron deficiency, dopamine dysregulation and inflammation.”
These proteins include a protein which transports vitamin D into cells and is involved in the regulation of dopamine levels, cystatin C – a biomarker for pain found in people with sciatica and during labor, and a neuromodulator (PTGDS) known to be involved in sleep disturbances. Levels of apolipoprotein (Apo) A1 were lower with RLS and may be related to the increased risk of cardiovascular disease.
The importance of iron’s role in RLS is highlighted by the presence of B-hemoglobin in the CSF of women with RLS, while levels of a glycoprotein (AGP) were reduced. AGP is involved in response to inflammatory damage and requires the presence of iron for it to be protective.
Dr Stephanie Patton continued, “Although a small study, this CSF protein profile is consistent with observed neuropathological findings and supports existing hypotheses about the biology behind RLS/WED, which could prove clinically important in developing new treatments.”
(Source: alphagalileo.org)
Unborn babies ‘practise’ facial expressions in the womb
Unborn babies ‘practise’ facial expressions of pain in the womb, according to a study published today.
The researchers from Durham and Lancaster Universities suggest that fetuses’ ability to show a “pain” facial expression is a developmental process which could potentially give doctors another index of the health of a fetus.
The study is published in the prestigious academic journal, PLOS ONE, and was part funded by the Economic and Social Research Council (ESRC) and Durham University.
The study extends the findings of previous work demonstrating that the facial expressions of healthy fetuses develop and become more complex during pregnancy resulting in fetuses being able to show recognisable facial expressions.
The 4D scans of 15 healthy fetuses showed that they develop from making very simple one-dimensional expressions at 24 weeks, such as moving their lips in order to form a “smile”, to complex multi-dimensional expressions which can be recognised as “pain” expressions, by the time the mother is 36 weeks into her pregnancy.
The researchers suggest this is an adaptive process which enables the unborn baby to prepare themselves for life after birth when they have to communicate, for example if they feel hungry or uncomfortable, by making grimaces or crying.
The researchers used the video footage of 4D scans, observing repeatedly the facial expressions of eight female and seven male fetuses from the second to third trimester (24 to 36 weeks) of pregnancy.
Fetuses observed at 24 weeks gestation rarely showed a combination of facial movements which make up a ‘pain face’, such as lowering the eyebrows, wrinkling the nose and stretching the mouth. However, by 36 weeks gestation, a combination of at least four movements was seen rather more frequently, giving the impression that these older fetuses were capable of making a pain face.
Lead researcher Dr Nadja Reissland, of Durham University’s Department of Psychology, said: “It is vital for infants to be able to show pain as soon as they are born so that they can communicate any distress or pain they might feel to their carers and our results show that healthy fetuses ‘learn’ to combine the necessary facial movements before they are born.
“This suggests that we can determine the normal development of facial movements and potentially identify abnormal development too. This could then provide a further medical indication of the health of the unborn baby.
“It is not yet clear whether fetuses can actually feel pain, nor do we know whether facial expressions relate to how they feel. Our research indicates that the expression of fetal facial movements is a developmental process which seems to be related to brain maturation rather than being linked to feelings.”
Professor of Social Statistics at Lancaster University Brian Francis said: “Modern methods of data analysis enable the development of fetal pain faces to be clearly detected, with the complexity of facial movements making up a pain face increasing in the third trimester”.
Despite the advances in medical science, we still do not know very much about health indicators of fetal development or any warning signs of delayed or abnormal progress in the womb.
It is hoped that further research will test whether the development of facial expressions is delayed if fetuses experience unhealthy conditions in the womb, such as effects of smoking or alcohol, or where the fetus is undergoing invasive procedures.
(Source: dur.ac.uk)
Research unveils insight into a debilitating brain disease
From the neurons that enable thought to the keratinocytes that make toenails grow-a complex canopy of sugar molecules, commonly known as glycans, envelop every living cell in the human body.
These complex carbohydrate chains perform a host of vital functions, providing the necessary machinery for cells to communicate, replicate and survive. It stands to reason, then, that when something goes wrong with a person’s glycans, something goes wrong with them.
Now, researchers at the University of Georgia are learning how changes in normal glycan behavior are related to a rare but fatal lysosomal disease known as Niemann-Pick type C (NPC), a genetic disorder that prevents the body from metabolizing cholesterol properly. The findings were published recently in the PNAS Early Edition.
"We are learning that the problems associated with cholesterol trafficking in the cell lead to problems with glycans on the cell’s surface, and that causes a multitude of negative effects," said Geert-Jan Boons, professor of chemistry in the Franklin College of Arts and Sciences and researcher at UGA’s Complex Carbohydrate Research Center. "Now, for the first time, we can see what these problems are, which we hope will lead to a new understanding of diseases like NPC."
Because NPC patients are unable to metabolize cholesterol, the waxy substance begins to accumulate in the brain. This can lead to a host of serious problems, including neurodegeneration, which the researchers hypothesize may be caused by improper recycling of glycans on the surface of an NPC patient’s cells.
Glycans normally undergo a kind of recycling process when they enter the cell only to be returned to the surface recharged and ready to work. The researchers discovered that glycans in NPC cells do not do this.
"One of the secondary effects of NPC is the disruption of traffic pathways within the cell, and this can lead to altered recycling of glycans," said Richard Steet, associate professor of biochemistry and molecular biology and CCRC researcher. "The glycans come into the cell, but they won’t recycle back up to the cell’s surface where they must exist to function as receptors or ion channels."
"Basically, the machinery gets clogged up," Boons said.
Like downed phone lines and flooded roads in a thunderstorm, glycans get stuck inside the cell making communication and travel for these cells difficult or impossible. Without these basic abilities, the body’s motor, sensory and cognitive functions begin to suffer. This might explain why NPC patients suffer from such a wide variety of neurological and psychiatric disorders, such as uncoordinated limb movements, slurred speech, epilepsy, paralysis, psychosis, dementia and hallucinations.
The researchers made these observations in fibroblasts taken from diseased patients. These cells are most commonly found in connective tissues, and they play a vital role in wound healing. However, they hope to continue their investigation into the effects of NPC by studying glycan behavior in neural cells, which make up the human brain.
While they caution that much more work must be done, they hope that an improved understanding of the roles that glycans play in neural cells will lead to new therapeutics for NPC and other diseases like it.
"It is exciting to work on projects like these, because we believe glycobiology is the next frontier, the next level of complexity," Boons said. "The time is right for new discovery."
(Source: news.uga.edu)
Scientists Coax Brain to Regenerate Cells Lost in Huntington’s Disease
Researchers have been able to mobilize the brain’s native stem cells to replenish a type of neuron lost in Huntington’s disease. In the study, which appears today in the journal Cell Stem Cell, the scientists were able to both trigger the production of new neurons in mice with the disease and show that the new cells successfully integrated into the brain’s existing neural networks, dramatically extending the survival of the treated mice.
“This study demonstrates the feasibility of a completely new concept to treat Huntington’s disease, by recruiting the brain’s endogenous neural stem cells to regenerate cells lost to the disease,” said University of Rochester Medical Center (URMC) neurologist Steve Goldman, M.D., Ph.D., co-director of Rochester’s Center for Translational Neuromedicine.
Huntington’s disease is an inherited neurodegenerative disease characterized by the loss of a specific cell type called the medium spiny neuron, a cell that is critical to motor control. The disease, which affects some 30,000 people in the U.S., results in involuntary movements, problems with coordination, and, ultimately, in cognitive decline and depression. There is currently no way to slow or modify this fatal disease.
For Goldman, the idea behind his strategy to treat the disease emerged from his decades-long study of neural plasticity in canaries. Songbirds like canaries have intrigued biologists because of their ability – unique in the animal kingdom – to lay down new neurons in the adult brain. This process, called adult neurogenesis, was first discovered by Goldman and Fernando Nottebohm of the Rockefeller University in the early 1980s, when the two realized that when learning new songs new neurons were added to regions of the bird’s brain responsible for vocal control.
“Our work with canaries essentially provided us with the information we needed to understand how to add new neurons to adult brain tissue,” said Goldman. “Once we mastered how this happened in birds, we set about how to replicate the process in the adult mammalian brain.”
Humans already possess the ability to create new neurons. Goldman’s lab demonstrated in the 1990s that a font of neuronal precursor cells exist in the lining of the ventricles, structures found in the core of the human brain. In early development, these cells are actively producing neurons. However, shortly after birth the neural stem cells stop generating neurons and instead produce glia, a family of support cells that pervade the central nervous system. Some parts of the human brain continue to produce neurons into adulthood, the most prominent example is the hippocampus where memories are formed and stored. But in the striatum, the region of the brain that is devastated by Huntington’s disease, this capability is “switched off” in adulthood.
Goldman and his team spent the past decade attempting to unravel the precise chemical signaling responsible for instructing neural stem cells when to create neurons and when to create glia cells. One of the most critical clues came directly from the earlier research with canaries. In the part of the bird’s brain were new songs are acquired and neurons added, the scientists observed the regulated expression of a protein called brain derived neurotrophic factor, or BDNF. When the production of this protein is triggered, the local neural stem cells are instructed to produce neurons.
At the same time, the scientists also realized that they had to simultaneously suppress the bias of these stem cells to produce glia. They found that when BDNF was combined with another molecule called noggin – a protein that inhibits the chemical pathway that dictates the creation of glial cells – they could successfully switch the stem cell’s molecular machinery over to the production of neurons.
The next challenge was how to deliver these two proteins – BDNF and noggin – precisely and in a sustained fashion to the area of the brain involved in Huntington’s disease. To do so, they partnered with scientists at the University of Iowa to modify a viral gene therapeutic, called an adeno-associated virus, to deliver the necessary molecular instructions to the neural stem cells.
The virus infected the target cells in the brains of mice with Huntington’s disease and triggered the sustained over-expression of both BDNF and noggin. This, in turn, activated the neighboring neural stem cells which began to produce medium spiny motor neurons. The new neurons were continuously generated and migrated to the striatum, the region of the brain impacted by Huntington’s disease, where they then integrated into the existing neuronal networks.
The researchers were able to significantly extend the survival of the treated mice, in some cases doubling their life expectancy. The researchers also devised a way to tag the new neurons and observed that the cells extended fibers to distant targets within the brain and establish electrical communication.
After having established the ability to generate new replacement neurons in mouse models of Huntington’s disease, the researchers also demonstrated that they could replicate this technique in the brains of normal squirrel monkeys, a step that brings the research much closer to tests in humans.
“The sustained delivery of BDNF and noggin into the adult brain was clearly associated with both increased neurogenesis and delayed disease progression,” said Goldman. “We believe that our data suggest the feasibility of this process as a viable therapeutic strategy for Huntington’s disease.”
![Evidence from a quiet MRI: Breastfeeding benefits babies’ brains
A study using brain images from “quiet” MRI machines adds to the growing body of evidence that breastfeeding improves brain development in infants. Breastfeeding alone produced better brain development than a combination of breastfeeding and formula, which produced better development than formula alone.
A new study by researchers from Brown University finds more evidence that breastfeeding is good for babies’ brains.
The study made use of specialized, baby-friendly magnetic resonance imaging (MRI) to look at the brain growth in a sample of children under the age of 4. The research found that by age 2, babies who had been breastfed exclusively for at least three months had enhanced development in key parts of the brain compared to children who were fed formula exclusively or who were fed a combination of formula and breastmilk. The extra growth was most pronounced in parts of the brain associated with language, emotional function, and cognition, the research showed.
This isn’t the first study to suggest that breastfeeding aids babies’ brain development. Behavioral studies have previously associated breastfeeding with better cognitive outcomes in older adolescents and adults. But this is the first imaging study that looked for differences associated with breastfeeding in the brains of very young and healthy children, said Sean Deoni, assistant professor of engineering at Brown and the study’s lead author.
“We wanted to see how early these changes in brain development actually occur,” Deoni said. “We show that they’re there almost right off the bat.”
The findings are in press in the journal NeuroImage and available now online.
Deoni leads Brown’s Advanced Baby Imaging Lab. He and his colleagues use quiet MRI machines that image babies’ brains as they sleep. The MRI technique Deoni has developed looks at the microstructure of the brain’s white matter, the tissue that contains long nerve fibers and helps different parts of the brain communicate with each other. Specifically, the technique looks for amounts of myelin, the fatty material that insulates nerve fibers and speeds electrical signals as they zip around the brain.
Deoni and his team looked at 133 babies ranging in ages from 10 months to four years. All of the babies had normal gestation times, and all came from families with similar socioeconomic statuses. The researchers split the babies into three groups: those whose mothers reported they exclusively breastfed for at least three months, those fed a combination of breastmilk and formula, and those fed formula alone. The researchers compared the older kids to the younger kids to establish growth trajectories in white matter for each group.
The study showed that the exclusively breastfed group had the fastest growth in myelinated white matter of the three groups, with the increase in white matter volume becoming substantial by age 2. The group fed both breastmilk and formula had more growth than the exclusively formula-fed group, but less than the breastmilk-only group.
“We’re finding the difference [in white matter growth] is on the order of 20 to 30 percent, comparing the breastfed and the non-breastfed kids,” said Deoni. “I think it’s astounding that you could have that much difference so early.”
Deoni and his team then backed up their imaging data with a set of basic cognitive tests on the older children. Those tests found increased language performance, visual reception, and motor control performance in the breastfed group.
The study also looked at the effects of the duration of breastfeeding. The researchers compared babies who were breastfed for more than a year with those breastfed less than a year, and found significantly enhanced brain growth in the babies who were breastfed longer — especially in areas of the brain dealing with motor function.
Deoni says the findings add to a substantial body of research that finds positive associations between breastfeeding and children’s brain health.
“I think I would argue that combined with all the other evidence, it seems like breastfeeding is absolutely beneficial,” he said.](http://40.media.tumblr.com/ada57cfdfa979a6b17b402976d2fd97b/tumblr_mo0jfjuSlS1rog5d1o1_500.jpg)
Evidence from a quiet MRI: Breastfeeding benefits babies’ brains
A study using brain images from “quiet” MRI machines adds to the growing body of evidence that breastfeeding improves brain development in infants. Breastfeeding alone produced better brain development than a combination of breastfeeding and formula, which produced better development than formula alone.
A new study by researchers from Brown University finds more evidence that breastfeeding is good for babies’ brains.
The study made use of specialized, baby-friendly magnetic resonance imaging (MRI) to look at the brain growth in a sample of children under the age of 4. The research found that by age 2, babies who had been breastfed exclusively for at least three months had enhanced development in key parts of the brain compared to children who were fed formula exclusively or who were fed a combination of formula and breastmilk. The extra growth was most pronounced in parts of the brain associated with language, emotional function, and cognition, the research showed.
This isn’t the first study to suggest that breastfeeding aids babies’ brain development. Behavioral studies have previously associated breastfeeding with better cognitive outcomes in older adolescents and adults. But this is the first imaging study that looked for differences associated with breastfeeding in the brains of very young and healthy children, said Sean Deoni, assistant professor of engineering at Brown and the study’s lead author.
“We wanted to see how early these changes in brain development actually occur,” Deoni said. “We show that they’re there almost right off the bat.”
The findings are in press in the journal NeuroImage and available now online.
Deoni leads Brown’s Advanced Baby Imaging Lab. He and his colleagues use quiet MRI machines that image babies’ brains as they sleep. The MRI technique Deoni has developed looks at the microstructure of the brain’s white matter, the tissue that contains long nerve fibers and helps different parts of the brain communicate with each other. Specifically, the technique looks for amounts of myelin, the fatty material that insulates nerve fibers and speeds electrical signals as they zip around the brain.
Deoni and his team looked at 133 babies ranging in ages from 10 months to four years. All of the babies had normal gestation times, and all came from families with similar socioeconomic statuses. The researchers split the babies into three groups: those whose mothers reported they exclusively breastfed for at least three months, those fed a combination of breastmilk and formula, and those fed formula alone. The researchers compared the older kids to the younger kids to establish growth trajectories in white matter for each group.
The study showed that the exclusively breastfed group had the fastest growth in myelinated white matter of the three groups, with the increase in white matter volume becoming substantial by age 2. The group fed both breastmilk and formula had more growth than the exclusively formula-fed group, but less than the breastmilk-only group.
“We’re finding the difference [in white matter growth] is on the order of 20 to 30 percent, comparing the breastfed and the non-breastfed kids,” said Deoni. “I think it’s astounding that you could have that much difference so early.”
Deoni and his team then backed up their imaging data with a set of basic cognitive tests on the older children. Those tests found increased language performance, visual reception, and motor control performance in the breastfed group.
The study also looked at the effects of the duration of breastfeeding. The researchers compared babies who were breastfed for more than a year with those breastfed less than a year, and found significantly enhanced brain growth in the babies who were breastfed longer — especially in areas of the brain dealing with motor function.
Deoni says the findings add to a substantial body of research that finds positive associations between breastfeeding and children’s brain health.
“I think I would argue that combined with all the other evidence, it seems like breastfeeding is absolutely beneficial,” he said.
Brain Imaging Study Eliminates Differences in Visual Function as a Cause of Dyslexia
A new brain imaging study of dyslexia shows that differences in the visual system do not cause the disorder, but instead are likely a consequence. The findings, published today in the journal Neuron, provide important insights into the cause of this common reading disorder and address a long-standing debate about the role of visual symptoms observed in developmental dyslexia.
Dyslexia is the most prevalent of all learning disabilities, affecting about 12 percent of the U.S. population. Beyond the primarily observed reading deficits, individuals with dyslexia often also exhibit subtle weaknesses in processing visual stimuli. Scientists have speculated whether these deficits represent the primary cause of dyslexia, with visual dysfunction directly impacting the ability to learn to read. The current study demonstrates that they do not.
“Our results do not discount the presence of this specific type of visual deficit,” says senior author Guinevere Eden, PhD, director for the Center for the Study of Learning at Georgetown University Medical Center (GUMC) and past-president of the International Dyslexia Association. “In fact our results confirm that differences do exist in the visual system of children with dyslexia, but these differences are the end-product of less reading, when compared with typical readers, and are not the cause of their struggles with reading.”
The current study follows a report published by Eden and colleagues in the journal Nature in 1996, the first study of dyslexia to employ functional Magnetic Resonance Imaging (fMRI). As in that study, the new study also shows less activity in a portion of the visual system that processes moving visual information in the dyslexics compared with typical readers of the same age.
This time, however, the research team also studied younger children without dyslexia, matched to the dyslexics on their reading level. “This group looked similar to the dyslexics in terms of brain activity, providing the first clue that the observed difference in the dyslexics relative to their peers may have more to do with reading ability than dyslexia per se,” Eden explains.
Next, the children with dyslexia received a reading intervention. Intensive tutoring of phonological and orthographic skills was provided, addressing the core deficit in dyslexia, which is widely believed to be a weakness in the phonological component of language. As expected, the children made significant gains in reading. In addition, activity in the visual system increased, suggesting it was mobilized by reading.
The researchers point out that these findings could have important implications for practice. “Early identification and treatment of dyslexia should not revolve around these deficits in visual processing,” says Olumide Olulade, PhD, the study’s lead author and post-doctoral fellow at GUMC. “While our study showed that there is a strong correlation between people’s reading ability and brain activity in the visual system, it does not mean that training the visual system will result in better reading. We think it is the other way around. Reading is a culturally imposed skill, and neuroscience research has shown that its acquisition results in a range of anatomical and functional changes in the brain.”
The researchers add that their research can be applied more broadly to other disorders. “Our study has important implications in understanding the etiology of dyslexia, but it also is relevant to other conditions where cause and consequence are difficult to pull apart because the brain changes in response to experience,” explains Eden.
(Source: explore.georgetown.edu)
MIT study sheds light on what causes compulsive behavior, could improve OCD treatments.
By activating a brain circuit that controls compulsive behavior, MIT neuroscientists have shown that they can block a compulsive behavior in mice — a result that could help researchers develop new treatments for diseases such as obsessive-compulsive disorder (OCD) and Tourette’s syndrome.
About 1 percent of U.S. adults suffer from OCD, and patients usually receive antianxiety drugs or antidepressants, behavioral therapy, or a combination of therapy and medication. For those who do not respond to those treatments, a new alternative is deep brain stimulation, which delivers electrical impulses via a pacemaker implanted in the brain.
For this study, the MIT team used optogenetics to control neuron activity with light. This technique is not yet ready for use in human patients, but studies such as this one could help researchers identify brain activity patterns that signal the onset of compulsive behavior, allowing them to more precisely time the delivery of deep brain stimulation.
“You don’t have to stimulate all the time. You can do it in a very nuanced way,” says Ann Graybiel, an Institute Professor at MIT, a member of MIT’s McGovern Institute for Brain Research and the senior author of a Science paper describing the study.
The paper’s lead author is Eric Burguière, a former postdoc in Graybiel’s lab who is now at the Brain and Spine Institute in Paris. Other authors are Patricia Monteiro, a research affiliate at the McGovern Institute, and Guoping Feng, the James W. and Patricia T. Poitras Professor of Brain and Cognitive Sciences and a member of the McGovern Institute.
Controlling compulsion
In earlier studies, Graybiel has focused on how to break normal habits; in the current work, she turned to a mouse model developed by Feng to try to block a compulsive behavior. The model mice lack a particular gene, known as Sapap3, that codes for a protein found in the synapses of neurons in the striatum — a part of the brain related to addiction and repetitive behavioral problems, as well as normal functions such as decision-making, planning and response to reward.
For this study, the researchers trained mice whose Sapap3 gene was knocked out to groom compulsively at a specific time, allowing the researchers to try to interrupt the compulsion. To do this, they used a Pavlovian conditioning strategy in which a neutral event (a tone) is paired with a stimulus that provokes the desired behavior — in this case, a drop of water on the mouse’s nose, which triggers the mouse to groom. This strategy was based on therapeutic work with OCD patients, which uses this kind of conditioning.
After several hundred trials, both normal and knockout mice became conditioned to groom upon hearing the tone, which always occurred just over a second before the water drop fell. However, after a certain point their behaviors diverged: The normal mice began waiting until just before the water drop fell to begin grooming. This type of behavior is known as optimization, because it prevents the mice from wasting unnecessary effort.
This behavior optimization never appeared in the knockout mice, which continued to groom as soon as they heard the tone, suggesting that their ability to suppress compulsive behavior was impaired.
The researchers suspected that failed communication between the striatum, which is related to habits, and the neocortex, the seat of higher functions that can override simpler behaviors, might be to blame for the mice’s compulsive behavior. To test this idea, they used optogenetics, which allows them to control cell activity with light by engineering cells to express light-sensitive proteins.
When the researchers stimulated light-sensitive cortical cells that send messages to the striatum at the same time that the tone went off, the knockout mice stopped their compulsive grooming almost totally, yet they could still groom when the water drop came. The researchers suggest that this cure resulted from signals sent from the cortical neurons to a very small group of inhibitory neurons in the striatum, which silence the activity of neighboring striatal cells and cut off the compulsive behavior.
“Through the activation of this pathway, we could elicit behavior inhibition, which appears to be dysfunctional in our animals,” Burguière says.
The researchers also tested the optogenetic intervention in mice as they groomed in their cages, with no conditioning cues. During three-minute periods of light stimulation, the knockout mice groomed much less than they did without the stimulation.
Scott Rauch, president and psychiatrist-in-chief of McLean Hospital in Belmont, Mass., says the MIT study “opens the door to a universe of new possibilities by identifying a cellular and circuitry target for future interventions.”
“This represents a major leap forward, both in terms of delineating the brain basis of pathological compulsive behavior and in offering potential avenues for new treatment approaches,” adds Rauch, who was not involved in this study.
Graybiel and Burguière are now seeking markers of brain activity that could reveal when a compulsive behavior is about to start, to help guide the further development of deep brain stimulation treatments for OCD patients.
Difficult-to-study diseases such as Alzheimer’s, schizophrenia, and autism now can be probed more safely and effectively thanks to an innovative new method for obtaining mature brain cells called neurons from reprogrammed skin cells. According to Gong Chen, the Verne M. Willaman Chair in Life Sciences and professor of biology at Penn State University and the leader of the research team, “the most exciting part of this research is that it offers the promise of direct disease modeling, allowing for the creation, in a Petri dish, of mature human neurons that behave a lot like neurons that grow naturally in the human brain.” Chen added that the method could lead to customized treatments for individual patients based on their own genetic and cellular information. The research will be published in the journal Stem Cell Research.
"Obviously, we don’t want to remove someone’s brain cells to experiment on, so recreating the patient’s brain cells in a Petri dish is the next best thing for research purposes and drug screening," Chen said. Chen explained that, in earlier work, scientists had found a way to reprogram skin cells from patients to become unspecialized or undifferentiated pluripotent stem cells (iPSCs). "A pluripotent stem cell is a kind of blank slate," Chen explained. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell. So, after generating iPSCs from skin cells, researchers then can culture them to become brain cells, or neurons, which can be studied safely in a Petri dish."
Now, in their new research, Chen and his team have found a way to differentiate iPSCs into mature human neurons much more effectively, generating cells that behave similarly to neurons in the brain. Chen explained that, in their natural environment, neurons are always found in close proximity to star-shaped cells called astrocytes, which are abundant in the brain and help neurons to function properly. “Because neurons are adjacent to astrocytes in the brain, we predicted that this direct physical contact might be an integral part of neuronal growth and health,” Chen explained.
To test this hypothesis, Chen and his colleagues began by culturing iPSC-derived neural stem cells, which are stem cells that have the potential to become neurons. These cells were cultured on top of a one-cell-thick layer of astrocytes so that the two cell types were physically touching each other.
"We found that these neural stem cells cultured on astrocytes differentiated into mature neurons much more effectively," Chen said, contrasting them with other neural stem cells that were cultured alone in a Petri dish. "It was almost as if the astrocytes were cheering the stem cells on, telling them what to do, and helping them fulfill their destiny to become neurons."
To demonstrate the superiority of the neurons grown next to astrocytes, Chen and his co-authors used an electrophysiology recording technique to show that the cells grown on astrocytes had many more synaptic events — signals sent out from one nerve cell to the others. In another experiment, after growing the neural stem cells next to astrocytes for just one week, the researchers showed that the newly differentiated neurons start to fire action potentials — the rapid electrical excitation signal that occurs in all neurons in the brain. In a final test, the team members added human neural stem cells to a mixture with mouse neurons. “We found that, after just one week, there was a lot of ‘cross-talk’ between the mouse neurons and the human neurons,” Chen said. He explained that “cross-talk” occurs when one neuron contacts its neighbors and releases a chemical called a neurotransmitter to modulate its neighbor’s activity.
"Previous researchers could only obtain brain cells from deceased patients who had suffered from diseases such as Alzheimer’s, schizophrenia, and autism," Chen said. "Now, researchers can take skin cells from living patients — a safe and minimally invasive procedure — and convert them into brain cells that mimic the activity of the patient’s own brain cells." Chen added that, by using this method, researchers also can figure out how a particular drug will affect a particular patient’s own brain cells, without needing the patient to try the drug — eliminating the risk of serious side effects. "The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly," Chen said.