Neuroscience
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This week, a strategic roadmap to help to the nation’s health care system cope with the impending public health crisis caused Alzheimer’s disease and related dementia will be published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. The plan aims to link the latest scientific findings with clinical care and bring together patients, families, scientists, pharmaceutical companies, regulatory agencies, and advocacy organizations behind a common set of prioritized goals. The consensus document is the outcome of a June meeting of leading Alzheimer’s researchers, advocates and clinicians, who gathered as part of the Marian S. Ware Alzheimer Program at the University of Pennsylvania.
Today, 5.4 million people are living with the disease, and more than 15 million Americans are caring for persons with Alzheimer’s and other dementias, according to the Alzheimer’s Association. Alzheimer’s disease is the sixth-leading cause of death in the United States and the only cause of death among the top 10 in the United States that cannot be prevented, cured, or even slowed.
"Our plan aims to provide good quality care for affected patients and families, advance our understanding of the pathophysiology and natural history of AD and other dementias, develop effective treatments to slow or prevent these diseases, and translate scientific advances successfully into policy and practice," the authors wrote.
New research offers a possible strategy for treating central nervous system diseases, such as brain and spinal cord injury, brain cancer, epilepsy, and neurological complications of HIV. The experimental treatment method allows small therapeutic agents to safely cross the blood-brain barrier in laboratory rats by turning off P-glycoprotein, one of the main gatekeepers preventing medicinal drugs from reaching their intended targets in the brain.
The findings appeared online Sept. 4 in the Proceedings of the National Academy of Sciences, and is the result of a study from scientists at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health.
“Many promising drugs fail because they cannot cross the blood-brain barrier sufficiently to provide a therapeutic dose to the brain,” said David Miller, Ph.D., head of the Laboratory of Toxicology and Pharmacology at NIEHS, and leader of the team that performed the study. “We hope our new strategy will have a positive impact on people with brain disorders in the future.”
In a two-pronged approach, the research team first determined that treating rat brain capillaries with the multiple sclerosis drug marketed as Gilenya (fingolimod) stimulated a specific biochemical signaling pathway in the blood-brain barrier that rapidly and reversibly turned off P-glycoprotein. Team members then pretreated rats with fingolimod, and administered three other drugs that P-glycoprotein usually transports away from the brain. They observed a dramatic decline in P-glycoprotein transport activity, which led to a threefold to fivefold increase in brain uptake for each of the three drugs.
Ronald Cannon, Ph.D., is a staff scientist in the Miller lab and first author on the paper. He said one of the burning questions the team wants to tackle next is to understand how the signaling system turns off P-glycoprotein. He equates the mechanism to what happens when a person flips a light switch.
“If you physically turn off a light using the button on the wall, the light will go out because the electrical current to the light bulb has been interrupted,” Cannon explained. “But what happens when the signaling pathway shuts down P-glycoprotein? Does it bring in another protein to bind to the pump, take away its energy source, modify the structure of the pump, or something else?”
Cannon said the paper’s findings open a new way of thinking regarding targets for drug design, a thought that is emotionally gratifying for him and many other researchers whose scientific discoveries generally don’t directly translate into helping people with illnesses.
“Although much more research needs to be done, delivering therapeutics to the central nervous system is one of the final frontiers of pharmacotherapy, Cannon added.”
When mice are born lacking the master gene Atoh1, none breathe well and all die in the newborn period. Why and how this occurs could provide new answers about sudden infant death syndrome (SIDS), but the solution has remained elusive until now.
Research led by Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital demonstrates that when the gene is lacking in a special population of neurons called RTN (retrotrapezoid nucleus), roughly half the young mice die at birth. Those who survive are less likely to respond to excess levels of carbon dioxide as adults. A report of their work appears online in the journal Neuron.
"The death of mice at birth clued us in that Atoh1 must be needed for the function of some neurons critical for neonatal breathing, so we set out to define these neurons," said Dr. Huda Zoghbi, senior author of the report and director of the Neurological Research Institute and a professor of molecular and human genetics, neuroscience, neurology and pediatrics at BCM. Zoghbi is also a Howard Hughes Medical Institute investigator.
"We took a genetic approach to find the critical neurons," said Wei-Hsiang Huang, a graduate student in the Program in Developmental Biology at BCM who works in Zoghbi’s laboratory. With careful studies to "knockout" the activity of the gene in a narrower and narrower area in the brain, they slowly eliminated possible neurons to determine that loss of Atoh1 in the RTN neurons was the source of the problem.
"Discovering that Atoh1 is indeed critical for the RTN neurons to take their right place in the brainstem and connect with the breathing center helped us uncover why they are important for neonatal breathing," said Zoghbi.
"This population of neurons resides in the ventral brainstem," said Huang. "When there is a change in the makeup of the blood (lack of oxygen or buildup of carbon dioxide), the RTN neurons sense that and tell the body to change the way it breathes." A defect in these neurons can disrupt this response.
"Without Atoh1 the mice have significant breathing problems because they do not automatically adjust their breathing to decrease carbon dioxide and oxygenate the blood," he said.
It turns out the findings from this mouse study are relevant to human studies.
"A paper just published reports that developmental abnormalities in the RTN neurons of children with sudden infant death syndrome or sudden unexplained intrauterine death may be linked to altered ventilatory response to carbon dioxide", said Huang (Lavezzi, A.M., et al., Developmental alterations of the respiratory human retrotrapezoid nucleus in sudden unexplained fetal and infant death, Auton. Neurosci. (2012), doi:10.1016/j.autneu.2012.06.005).
In mice, added amino acid reduced associated epilepsy, eased neurobehavioral symptom
An international team of researchers, led by scientists at the University of California, San Diego and Yale University schools of medicine, have identified a form of autism with epilepsy that may potentially be treatable with a common nutritional supplement.
The findings are published in the September 6, 2012 online issue of Science.
Roughly one-quarter of patients with autism also suffer from epilepsy, a brain disorder characterized by repeated seizures or convulsions over time. The causes of the epilepsy are multiple and largely unknown. Using a technique called exome sequencing, the UC San Diego and Yale scientists found that a gene mutation present in some patients with autism speeds up metabolism of certain amino acids. These patients also suffer from epileptic seizures. The discovery may help physicians diagnose this particular form of autism earlier and treat sooner.
The researchers focused on a specific type of amino acid known as branched chain amino acids or BCAAs. BCAAs are not produced naturally in the human body and must be acquired through diet. During periods of starvation, humans have evolved a means to turn off the metabolism of these amino acids. It is this ability to shut down that metabolic activity that researchers have found to be defective in some autism patients.
“It was very surprising to find mutations in a potentially treatable metabolic pathway specific for autism,” said senior author Joseph G. Gleeson, MD, professor in the UCSD Department of Neurosciences and Howard Hughes Medical Institute investigator. “What was most exciting was that the potential treatment is obvious and simple: Just give affected patients the naturally occurring amino acids their bodies lack.”
Gleeson and colleagues used the emerging technology of exome sequencing to study two closely related families that have children with autism spectrum disorder. These children also had a history of seizures or abnormal electrical brain wave activity, as well as a mutation in the gene that regulates BCAAs. In exome sequencing, researchers analyze all of the elements in the genome involved in making proteins.
In addition, the scientists examined cultured neural stem cells from these patients and found they behaved normally in the presence of BCAAs, suggesting the condition might be treatable with nutritional supplementation. They also studied a line of mice engineered with a mutation in the same gene, which showed the condition was both inducible by lowering the dietary intake of the BCAAs and reversible by raising the dietary intake. Mice treated with BCAA supplementation displayed improved neurobehavioral symptoms, reinforcing the idea that the approach could work in humans as well.
“Studying the animals was key to our discovery,” said first author Gaia Novarino, PhD, a staff scientist in Gleeson’s lab. “We found that the mice displayed a condition very similar to our patients, and also had spontaneous epileptic seizures, just like our patients. Once we found that we could treat the condition in mice, the pressing question was whether we could effectively treat our patients.”
Using a nutritional supplement purchased at a health food store at a specific dose, the scientists reported that they could correct BCAA levels in the study patients with no ill effect. The next step, said Gleeson, is to determine if the supplement helps reduce the symptoms of epilepsy and/or autism in humans.
“We think this work will establish a basis for future screening of all patients with autism and/or epilepsy for this or related genetic mutations, which could be an early predictor of the disease,” he said. “What we don’t know is how many patients with autism and/or epilepsy have mutations in this gene and could benefit from treatment, but we think it is an extremely rare condition.”
September 5, 2012 by Michael C. Purdy
Sleep disruptions may be among the earliest indicators of Alzheimer’s disease, scientists at Washington University School of Medicine in St. Louis report Sept. 5 in Science Translational Medicine.
Working in a mouse model, the researchers found that when the first signs of Alzheimer’s plaques appear in the brain, the normal sleep-wake cycle is significantly disrupted.
“If sleep abnormalities begin this early in the course of human Alzheimer’s disease, those changes could provide us with an easily detectable sign of pathology,” says senior author David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of Washington University’s Department of Neurology. “As we start to treat Alzheimer’s patients before the onset of dementia, the presence or absence of sleep problems may be a rapid indicator of whether the new treatments are succeeding.”
Holtzman’s laboratory was among the first to link sleep problems and Alzheimer’s through studies of sleep in mice genetically altered to develop Alzheimer’s plaques as they age. In a study published in 2009, he showed that brain levels of a primary ingredient of the plaques naturally rise when healthy young mice are awake and drop after they go to sleep. Depriving the mice of sleep disrupted this cycle and accelerated the development of brain plaques.
A similar rising and falling of the plaque component, a protein called amyloid beta, was later detected in the cerebrospinal fluid of healthy humans studied by co-author Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University.
The new research, led by Jee Hoon Roh, MD, PhD, a neurologist and postdoctoral fellow in Holtzman’s laboratory, shows that when the first indicators of brain plaques appear, the natural fluctuations in amyloid beta levels stop in both mice and humans.
“We suspect that the plaques are pulling in amyloid beta, removing it from the processes that would normally clear it from the brain,” Holtzman says.
Mice are nocturnal animals and normally sleep for 40 minutes during every hour of daylight, but when Alzheimer’s plaques began forming in their brains, their average sleep times dropped to 30 minutes per hour.
To confirm that amyloid beta was directly linked to the changes in sleep, researchers gave a vaccine against amyloid beta to a new group of mice with the same genetic modifications. As these mice grew older, they did not develop brain plaques. Their sleeping patterns remained normal and amyloid beta levels in the brain continued to rise and fall regularly.
Scientists now are evaluating whether sleep problems occur in patients who have markers of Alzheimer’s disease, such as plaques in the brain, but have not yet developed memory or other cognitive problems.
“If these sleep problems exist, we don’t yet know exactly what form they take—reduced sleep overall or trouble staying asleep or something else entirely,” Holtzman says. “But we’re working to find out.”
A North Carolina State University researcher has created a roadmap to areas of the brain associated with affective aggression in mice. This roadmap may be the first step toward finding therapies for humans suffering from affective aggression disorders that lead to impulsive violent acts.
Affective aggression differs from defensive aggression or premeditated aggression used by predators, in that the role of affective aggression isn’t clear and could be considered maladaptive. NC State neurobiologist Dr. Troy Ghashghaei was interested in finding the areas of the brain engaged with this type of aggressive behavior. Using mice that had been specially bred for affective aggression by his research associate Dr. Derrick L Nehrenberg, Ghashghaei and former undergraduate student Atif Sheikh were able to locate the regions in the mouse brain that switched on and those that were off when the mice displayed affective aggression.
“The brain works by using clusters of neurons that cross communicate at extremely rapid rates, much like a computer,” Ghashghaei explains. “One region will process a stimulus, and then that region sends messages to other clusters within the brain, like circuits within a computer. We looked at how the switches flipped in the brains of aggressive mice, and compared that with the brains of completely nonaggressive mice in the same setting, to see how the two processed the situation differently.”
They found that affectively aggressive mice demonstrated a large difference in the way their “executive centers” operated when the mice encountered another mouse. “Sensory inputs come in and are sent to the executive center, the part of the brain that decides how to respond to the input,” Ghashghaei says. “In the meantime, the information about the response you made gets processed back with either a pleasant or unpleasant association.”
According to Ghashghaei, the affectively aggressive mice could react violently because their brains are hardwiredto respond to certain situations aggressively without assessing whether their response to the situation is appropriate or without regard to the behavior’s consequences. In addition, affectively aggressive mice may be forming pleasant associations with their violent displays, which would reinforce their aggressive tendencies.
“We cannot say which of the two possibilities underlie the persistent aggressive displays by our mice,” Ghashghaei says, “but we can see that the patterns of neuronal activity are very different in the executive centers of these mice. Additionally, there are differences in the neuronal clusters involved with creating pleasant or unpleasant associations to the stimulus or their response. That gives us a few starting spots to begin identifying the mechanisms that underlie these profound behavioral differences.”
The regions of the brain that were involved in affective aggression in the mice are similar across all mammalian species. Ghashghaei hopes that his findings in mice will be useful to researchers studying violent behavior in humans, as well as aggression in other animals.
“With the brain, just knowing where to start looking is huge,” Ghashghaei says. “Once you have a few targets, you can tease out the possibilities and get to the heart of the problem. We are confident that manipulation of some of the identified targets in our study will disrupt displays of affective aggression in our mouse model.”
A new University of Wisconsin-Madison imaging study shows the brains of people with generalized anxiety disorder (GAD) have weaker connections between a brain structure that controls emotional response and the amygdala, which suggests the brain’s “panic button” may stay on due to lack of regulation.
Anxiety disorders are the most common class of mental disorders and GAD, which is characterized by excessive, uncontrollable worry, affects nearly 6 percent of the population.
Lead author Dr. Jack Nitschke, associate professor of psychiatry in the UW School of Medicine and Public Health, says the findings support the theory that reduced communications between parts of the brain explains the intense anxiety felt by people with GAD.
In this case, two types of scans showed the amygdala, which alerts us to threat in our surroundings and initiates the “fight-or-flight” response, seems to have weaker “white matter” connections to the prefrontal and anterior cingulate cortex (ACC), the center of emotional regulation.
The researchers did two types of imaging - diffusion tensor imaging (DTI) and functional magnetic resonance (fMRI) - on the brains of 49 GAD patients and 39 healthy volunteers. Compared with the healthy volunteers, the imaging showed the brains of people with GAD had reduced connections between the prefrontal and anterior cingulate cortex and the amygdala via the uncinate fasciculus, a primary “white matter” tract that connects these brain regions. This reduced connectivity was not found in other white matter tracts elsewhere in their brains.
"We know that in the brain, if you use a circuit you build it up, the way you build muscle by exercise,” says Nitschke, a clinical psychologist who treats patients with anxiety disorders and does research at the UW-Madison’s Waisman Center.
Nitschke says that researchers wonder if this weak connection results in the intense anticipatory anxiety and worry that is the hallmark of GAD, because the ACC is unable to tell the amygdala to “chill out.” It also suggests that behavioral therapy that teaches patients to consciously exercise this emotional regulation works to reduce anxiety by strengthening the connection.
"It’s possible that this is exactly what we’re doing when we teach patients to regulate their reactions to the negative events that come up in everyone’s lives,” Nitschke says. "We can help build people’s tolerance to uncontrollable future events by teaching them to regulate their emotions to the uncertainty that surrounds those events.
03 September 2012 by Andy Coghlan
For the first time, people with broken spines have recovered feeling in previously paralysed areas after receiving injections of neural stem cells.
(Image: Medical Images/Getty Images)
Three people with paralysis received injections of 20 million neural stem cells directly into the injured region of their spinal cord. The cells, acquired from donated fetal brain tissue, were injected between four and eight months after the injuries happened. The patients also received a temporary course of immunosuppressive drugs to limit rejection of the cells.
None of the three felt any sensation below their nipples before the treatment. Six months after therapy, two of them had sensations of touch and heat between their chest and belly button. The third patient has not seen any change.
"The fact we’ve seen responses to light touch, heat and electrical impulses so far down in two of the patients is very unexpected," says Stephen Huhn of StemCells, the company in Newark, California, developing and testing the treatment. "They’re really close to normal in those areas now in their sensitivity," he adds.
"We are very intrigued to see that patients have gained considerable sensory function," says Armin Curt of Balgrist University Hospital in Zurich, Switzerland, where the patients were treated, and principal investigator in the trial.
The data are preliminary, but “these sensory changes suggest that the cells may be positively impacting recovery”, says Curt, who presented the results today in London at the annual meeting of the International Spinal Cord Society.
3-Sep-2012
Researchers at Emory University have found that a medication that inhibits inflammation may offer new hope for people with difficult-to-treat depression. The study was published Sept. 3 in the online version of Archives of General Psychiatry.
"Inflammation is the body’s natural response to infection or wounding, says Andrew H. Miller, MD, senior author for the study and professor of Psychiatry and Behavioral Sciences at Emory University School of Medicine. "However when prolonged or excessive, inflammation can damage many parts of the body, including the brain."
Prior studies have suggested that depressed people with evidence of high inflammation are less likely to respond to traditional treatments for the disorder, including anti-depressant medications and psychotherapy. This study was designed to see whether blocking inflammation would be a useful treatment for either a wide range of people with difficult-to-treat depression or only those with high levels of inflammation.
The study employed infliximab, one of the new biologic drugs used to treat autoimmune and inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. A biologic drug copies the effects of substances naturally made by the body’s immune system. In this case, the drug was an antibody that blocks tumor necrosis factor (TNF), a key molecule in inflammation that has been shown to be elevated in some depressed individuals.
Study participants all had major depression and were moderately resistant to conventional antidepressant treatment. Each participant was assigned either to infliximab or to a non-active placebo treatment.
When investigators looked at the results for the group as a whole, no significant differences were found in the improvement of depression symptoms between the drug and placebo groups. However, when the subjects with high inflammation were examined separately, they exhibited a much better response to infliximab than to placebo.
Inflammation in this study was measured using a simple blood test that is readily available in most clinics and hospitals and measures C-reactive protein or CRP. The higher the CRP, the higher the inflammation, and the higher the likelihood of responding to the drug.
"The prediction of an antidepressant response using a simple blood test is one of the holy grails in psychiatry," says Miller. "This is especially important because the blood test not only measured what we think is at the root cause of depression in these patients, but also is the target of the drug."
"This is the first successful application of a biologic therapy to depression," adds Charles L. Raison, MD, first author of the study. "The study opens the door to a host of new approaches that target the immune system to treat psychiatric diseases." Raison, formerly at Emory, is now associate professor in the Department of Psychiatry at the University of Arizona College of Medicine – Tucson.
September 3, 2012
People whose blood sugar is on the high end of the normal range may be at greater risk of brain shrinkage that occurs with aging and diseases such as dementia, according to new research published in the September 4, 2012, print issue of Neurology, the medical journal of the American Academy of Neurology.
"Numerous studies have shown a link between type 2 diabetes and brain shrinkage and dementia, but we haven’t known much about whether people with blood sugar on the high end of normal experience these same effects," said study author Nicolas Cherbuin, PhD, with Australian National University in Canberra.
The study involved 249 people age 60 to 64 who had blood sugar in the normal range as defined by the World Health Organization. The participants had brain scans at the start of the study and again an average of four years later.
Those with higher fasting blood sugar levels within the normal range and below 6.1 mmol/l (or 110 mg/dL) were more likely to have a loss of brain volume in the areas of the hippocampus and the amygdala, areas that are involved in memory and cognitive skills, than those with lower blood sugar levels. A fasting blood sugar level of 10.0 mmol/l (180 mg/dL) or higher was defined as diabetes and a level of 6.1 mmol/l (110 mg/dL) was considered impaired, or prediabetes.
After controlling for age, high blood pressure, smoking, alcohol use and other factors, the researchers found that blood sugar on the high end of normal accounted for six to 10 percent of the brain shrinkage.
"These findings suggest that even for people who do not have diabetes, blood sugar levels could have an impact on brain health," Cherbuin said. "More research is needed, but these findings may lead us to re-evaluate the concept of normal blood sugar levels and the definition of diabetes."
Source: medicalxpress.com
ScienceDaily (Sep. 3, 2012) — A new study by researchers at NYU School of Medicine reveals for the first time that metabolic syndrome (MetS) is associated with cognitive and brain impairments in adolescents and calls for pediatricians to take this into account when considering the early treatment of childhood obesity.
The study, funded by the National Institutes of Health under award number DK083537, and in part by award number 1ULIRR029892, from the National Center for Research Resources, appears online September 3 in Pediatrics.
As childhood obesity has increased in the U.S., so has the prevalence of metabolic syndrome — a constellation of three or more of five defined health problems, including abdominal obesity, low HDL (good cholesterol), high triglycerides, high blood pressure and pre-diabetic insulin resistance. Lead investigator Antonio Convit, MD, professor of psychiatry and medicine at NYU School of Medicine and a member of the Nathan Kline Research Institute, and colleagues have shown previously that metabolic syndrome has been linked to neurocognitive impairments in adults, but this association was generally thought to be a long-term effect of poor metabolism. Now, the research team has revealed even worse brain impairments in adolescents with metabolic syndrome, a group absent of clinically-manifest vascular disease and likely shorter duration of poor metabolism.
"The prevalence of MetS parallels the rise in childhood obesity," Dr. Convit said. "There are huge numbers of people out there who have problems with their weight. If those problems persist long enough, they will lead to the development of MetS and diabetes. As yet, there has been very little information available about what happens to the brain in the setting of obesity and MetS and before diabetes onset in children."
Electrodes inside the skull can temporarily mimic brain disease – and so allow us to find out more about the way we work
Second thoughts: electrodes are inserted into a patient’s brain. Photograph: University of Utah Department of Neurosurgery
The first person to electrically stimulate the brain of a living human during surgery was the 19th-century British neurosurgeon Sir Victor Horsley. The operation was to treat a deformation called an encephalocele, where the bones of the skull do not close properly in the womb, causing the brain to protrude from the head. Horsely applied a weak electrical current to the surgically exposed brain tissue, making the patient’s eyes swivel to the side, which told the surgeon that the out-of-place area was the top of the midbrain – normally a deeply embedded neural structure essential for directing vision.
The technique was later picked up to treat epilepsy as it became clear that removing the part of the brain that triggered seizures could be an effective treatment, even if identifying it could be tricky. Small, clearly identified points of damage or localised tumours could often trigger seizures but sometimes the errant waves of epileptic activity would start far away from the original point of visible injury. Horsley used the electrical stimulation technique while patients were awake to find the sensitive area and remove it. Not bad for 1886.
Although initially invented for medical reasons, this surgical technique began to throw up some curious scientific data. In the 1930s the Canadian neurosurgeon Wilder Penfield asked patients undergoing epilepsy surgery if he could perform brief experiments while they were being operated on. He found that stimulating parts of the brain could cause a range of reactions from tingling to weeping to a “desire to move” – providing crucial evidence that activity in specific brain areas could trigger surprisingly complex behaviours.
People with epilepsy have remained an important part of our quest to understand ourselves as they have regularly volunteered to take part in neuroscience experiments while undergoing open-brain operations. Even though these experiments are a relatively brief pause in the procedure, they still require people to offer some of their time while their skull has been opened and their brain exposed, and we know much more about the brain thanks to their generosity.
As surgical techniques have moved on, so has the science. The starting points of some seizures are not easily located in the relatively short period available during surgery. To compensate for this, neurosurgeons have taken to implanting electrodes in the brains of people with epilepsy before the skull is replaced and the skin sewn up, which allows the medical team to record brain activity as the patients go about their daily life. One form of this “in brain” recording, known as electrocorticography, involves surgically inserting a grid of electrodes over the surface of the brain.
This has allowed neuroscientists to measure the brain at work in the real world via cables that go from the brain into a small digital recorder. A study published last year in the Journal of Neurosurgery mapped the main language areas of the cortex, the brain’s outer layer, using an implanted electrode grid and a simple word task that took an average of just 47 seconds. More than 100 other studies have used this technique with similarly impressive results.
One innovation is particularly mind-boggling. After years of using implanted electrode grids to read from the brain, neuroscientists have begun to use the electrodes to write to it – in other words, to alter the function of the brain through the same electrodes that record its activity. “By having a grid of electrodes in place,” says Matthew Lambon Ralph, professor of cognitive neuroscience at Manchester University, “it is possible to probe many different regions rather than just one.”
The precision is such that the Lambon Ralph team and a team at Kyoto University Medical School, led by Riki Matsumoto, have used an implanted grid to temporarily simulate characteristics of a brain disease called semantic dementia. Like Alzheimer’s, semantic dementia is a degenerative disorder, but one in which brain cells that specifically support our understanding of meaning rapidly decline. Studies of patients with semantic dementia have taught us a great deal about how memory is organised in the brain but the disorder is swift and unpredictable, and a method that can mimic the effects while recording directly from the cortex is a powerful tool.
The technique is safe and reversible, as we know from a simple version that is often done pre-neurosurgery to ensure that no tissue that supports key mental functions is removed during the operation. Using it as a way of briefly simulating more complex cognitive difficulties is an exciting development. “Stimulation is injected in one part of a grid and the evoked response across other grids is measured. It’s a direct measure of functional connectivity,” explains Lambon Ralph, highlighting how these sorts of studies can allow the brain’s function, in terms of thinking skills, to be closely linked to its physical connections.
The research was presented at the British Neuropsychological Society spring conference by UK-based team member Taiji Ueno. The main findings are still being prepared for peer review but the use of implant grids in neuroscience research is sure to become more common as the surgical procedure becomes more widely used.
These procedures are only done for medical reasons, and researchers get no say about how and on whom they are performed. But, as ever, patients have been generous with their time. From 1886 until now, these exciting discoveries have been made possible by people on the operating table.
Picower Institute for Learning and Memory Neuroscientist Matt Wilson has shown not only that animals dream, but that they dream about what they experience. In a lab rat’s world, that means navigating mazes. In Wilson’s latest study, slated to appear Sept. 2 in Nature Neuroscience, researchers manipulated the content of rodent dreams by replaying an audio cue that accompanied that day’s maze.
Matthew Wilson, the Sherman Fairchild Professor of Neuroscience and a member of the Picower Institute for Learning and Memory at MIT. Photo: Patrick Gillooly
In a study — led by Daniel Bendor, Picower Institute postdoctoral fellow, and Wilson, the Associate Department Head for Education and Sherman Fairchild Professor of Neuroscience in MIT’s Department of Brain and Cognitive Sciences — rats were trained to run a maze using audio cues: one sound directed the animal to run to the right end of the track for a reward and a different sound meant the reward could be found on the left.
As the animals slept, researchers recorded the activity of specific neurons within their brains that allowed them to see, as in previous experiments, that the animals’ dreams were a replay of the maze-running task they had learned while awake. Except this time, when the researchers played the audio cues into the cages of the slumbering rodents, the rats were more likely to dream about the section of the maze previously associated with the audio cue.
“Our most recent experiments demonstrate the ability to bias the content of reactivated memory during sleep to specific past experiences. This could be thought of as a simple form of dream engineering and opens up the possibility of more extensive control of memory processing during sleep to enhance selected memories and to block or modify unwanted memories,” the researchers wrote.
Wilson’s lab, which aims to establish the role of sleep in memory and cognition, hopes the knowledge will lead to new approaches to learning and behavioral therapy through manipulation of brain systems during sleep.
Source: MIT
ScienceDaily (Sep. 1, 2012) — Flying high, or down in the dumps — individuals suffering from bipolar disorder alternate between depressive and manic episodes. Researchers from the University of Bonn and the Central Institute of Mental Health in Mannheim have now discovered, based on patient data and animal models, how the NCAN gene results in the manic symptoms of bipolar disorder.
(Credit: © Bastos / Fotolia)
The results have been published in the current issue of The American Journal of Psychiatry.
Individuals with bipolar disorder are on an emotional roller coaster. During depressive phases, they suffer from depression, diminished drive and often, also from suicidal thoughts. The manic episodes, however, are characterized by restlessness, euphoria, and delusions of grandeur. The genesis of this disease probably has both hereditary components as well as psychosocial environmental factors.
The NCAN gene plays a major part in how manias manifest
"It has been known that the NCAN gene plays an essential part in bipolar disorder," reports Prof. Dr. Markus M. Nöthen, Director of the Institute of Human Genetics at the University of Bonn. "But until now, the functional connection has not been clear." In a large-scale study, researchers led by the University of Bonn and the Central Institute of Mental Health in Mannheim have now shown how the NCAN gene contributes to the genesis of mania. To do so, they evaluated the genetic data and the related descriptions of symptoms from 1218 patients with differing ratios between the manic and depressive components of bipolar disorder.
Comprehensive data from patients and animal models
Using the patients’ detailed clinical data, the researchers tested statistically which of the symptoms are especially closely related to the NCAN gene. “Here it became obvious that the NCAN gene is very closely and quite specifically correlated with the manic symptoms,” says Prof. Dr. Marcella Rietschel from the Central Institute of Mental Health in Mannheim. According to the data the gene is, however, not responsible for the depressive episodes in bipolar disorder.
Manic mice drank from sugar solution with abandon
A team working with Prof. Dr. Andreas Zimmer, Director of the Institute of Molecular Psychiatry at the University of Bonn, examined the molecular causes effected by the NCAN gene. The researchers studied mice in which the gene had been “knocked out.” “It was shown that these animals had no depressive component in their behaviors, only manic ones,” says Prof. Zimmer. These knockout mice were, e.g., considerably more active than the control group and showed a higher level of risk-taking behavior. In addition, they tended to exhibit increased reward-seeking behavior, which manifested itself by their unrestrained drinking from a sugar solution offered by the researchers.
Lithium therapy also effective against hyperactivity in mice
Finally, the researchers gave the manic knockout mice lithium — a standard therapy for humans. “The lithium dosage completely stopped the animals’ hyperactive behavior,” reports Prof. Zimmer. So the results also matched for lithium; the responses of humans and mice regarding the NCAN gene were practically identical. It has been known from prior studies that knocking out the NCAN gene results in a developmental disorder in the brain due to the fact that the production of the neurocan protein is stopped. “As a consequence of this molecular defect, the individuals affected apparently develop manic symptoms later,” says Prof. Zimmer.
Opportunity for new therapies
Now the scientists want to perform further studies of the molecular connections of this disorder — also with a view towards new therapies. “We were quite surprised to see how closely the findings for mice and the patients correlated,” says Prof. Nöthen. “This level of significance is very rare.” With a view towards mania, the agreement between the findings opens up the opportunity to do further molecular studies on the mouse model, whose results will very likely also be applicable to humans. “This is a great prerequisite for advancing the development of new drugs for mania therapy,” believes Prof. Rietschel.
Source: Science Daily