Posts tagged epilepsy
Articles and news from the latest research reports.
Anti-epilepsy drugs can cause inflammations
Glial cells play a crucial role in the nervous system
Hannes Dambach from the Department for Neuroanatomy and Molecular Brain Research, together with a team of colleagues, studied how anti-epilepsy drugs affect the survival of glial cells in cultures. Glial cells are the largest cell group in the brain; they are crucial for supplying neurons with nutrients and affect immune and inflammatory responses. The question of how glial cells are affected by anti-epilepsy drugs had previously not been studied in depth. The RUB work group Clinical Neuroanatomy, headed by Prof Dr Pedro Faustmann, analysed four substances: valproic acid, gabapentin, phenytoin and carbamazepine.
Four anti-epilepsy drugs affect glial cells in different ways
Glial cells treated by the researchers with valproic adic and gabapentin had better survival chances than those treated with phenytoin and carbamazepine. However, carbamazepine had a positive effect, too: it reduced inflammatory responses. Valproic acid, on the other hand, turned out to be pro-inflammatory. In how far the anti-epilepsy drugs affected inflammations was also determined by the applied dose. Consequently, different drugs affected glial cells – and hence indirectly the neurons – in different ways.
Inflammatory responses should be taken under consideration in clinical studies
“Clinical studies should focus not only on the question in how far anti-epilepsy drugs affect the severity and frequency of epileptic seizures,” says Pedro Faustmann. “It is also necessary to test them with regard to the role they play in inflammatory responses in the central nervous system.” Thus, doctors could take the underlying inflammatory condition under consideration when selecting the right anti-epilepsy drug.
Epilepsy may have different causes
In Germany, between 0.5 and 1 percent of the population suffer from epilepsy that requires drug treatment. The disease may have many causes: genetic predisposition, disorders of the central nervous system after meningitis, traumatic brain injury and stroke. Inflammatory responses may also be caused by damage to the brain.
Study looks at better prediction for epileptic seizures through adaptive learning approach
A UT Arlington assistant engineering professor has developed a computational model that can more accurately predict when an epileptic seizure will occur next based on the patient’s personalized medical information.
The research conducted by Shouyi Wang, an assistant professor in the Department of Industrial and Manufacturing Systems Engineering, has been in the paper “Online Seizure Prediction Using an Adaptive Learning Approach” in IEEE Transactions on Knowledge and Data Engineering.
Wang’s model analyzes electroencephalography, or EEG, readings from an individual, to predict future seizures. Early warnings could lead a patient to use medicine to combat an oncoming seizure, he said.
“The challenge with seizure prediction has been that every epileptic is different. Some patients suffer several seizures a day. Others will go several years without experiencing a seizure,” Wang said. “But if we use the EEG readings to build a personalized data profile, we’re better able to understand what’s happening to that person.”
Epilepsy is one of the most common neurological disorders, characterized by recurrent seizures. Epilepsy and seizures affect nearly 3 million Americans at an estimated annual cost of $17.6 billion in direct and indirect costs, according to the national Epilepsy Foundation, About 10 percent of the American population will experience a seizure in their lifetime, the agency says.
Wang teamed with Wanpracha Art Chaovalitwongse of the University of Washington and Stephen Wong of the Rutgers Robert Wood Johnson Medical School for the research.
Wang said early indications are that the new computational model could provide 70 percent accuracy or better and give a prediction horizon of about 30 minutes before the actual seizure would occur.
The current model collects data through a cap embedded with EEG wires. Wang’s team is working to develop a less obtrusive EEG cap that will record and transmit readings to a box for easy data download or transmission.
Victoria Chen, professor and chairwoman of the Industrial and Manufacturing Systems Engineering Department, said Wang’s work in the area of bioinformatics offers hope for the many people who suffer from epilepsy.
“This computational model might be used to predict other life-threatening episodes of diseases,” Chen said.
Wang said his model builds upon an adaptive learning framework and is capable of achieving more and more accurate prediction performance for each individual patientby collecting more and more personalized medical data.
“As a society, we’ve gotten really good at looking at the big picture,” Wang said. “We can tell you the likelihood of suffering a heart attack if you’re over a certain age, of a certain weight and if you smoke. But we have only started to personalize that data for individuals who are all different.”
Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals.
"We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team’s findings. “We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally.”
The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD.
By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown.
"It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment."
"We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs.
To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs.
"At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says.
Study finds altered brain connections in epilepsy patients
Patients with the most common form of focal epilepsy have widespread, abnormal connections in their brains that could provide clues toward diagnosis and treatment, according to a new study published online in the journal Radiology.
(Image: MP-RAGE volumes are segmented into 83 ROIs, which are further parcellated into 1000 cortical and 15 subcortical ROIs. Whole-brain white matter tractography is performed after voxelwise tensor calculation, and the density of fibers that connect each pair of cortical ROIs is used to calculate structural connectivity. T1w = T1-weighted. Credit: Courtesy of Radiology and RSNA)
Temporal lobe epilepsy is characterized by seizures emanating from the temporal lobes, which sit on each side of the brain just above the ear. Previously, experts believed that the condition was related to isolated injuries of structures within the temporal lobe, like the hippocampus. But recent research has implicated the default mode network (DMN), the set of brain regions activated during task-free introspection and deactivated during goal-directed behavior. The DMN consists of several hubs that are more active during the resting state.
To learn more, researchers performed diffusion tensor imaging, a type of MRI that tracks the movement, or diffusion, of water in the brain’s white matter, the nerve fibers that transmit signals throughout the brain. The study group consisted of 24 patients with left temporal lobe epilepsy who were slated for surgery to remove the site from where their seizures emanated. The researchers compared them with 24 healthy controls using an MRI protocol dedicated to finding white matter tracts with diffusion imaging at high resolution. The data was analyzed with a new technique that identifies and quantifies structural connections in the brain.
Patients with left temporal lobe epilepsy exhibited a decrease in long-range connectivity of 22 percent to 45 percent among areas of the DMN when compared with the healthy controls.
"Using diffusion MRI, we found alterations in the structural connectivity beyond the medial temporal lobe, especially in the default mode network," said Steven M. Stufflebeam, M.D., from the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston.
In addition to reduced long-range connectivity, the epileptic patients had an 85 percent to 270 percent increase in local connectivity within and beyond the DMN. The researchers believe this may be an adaptation to the loss of the long-range connections.
"The increase in local connections could represent a maladaptive mechanism by which overall neural connectivity is maintained despite the loss of connections through important hub areas," Dr. Stufflebeam said.
The results are supported by prior functional MRI studies that have shown decreased functional connectivity in DMN areas in temporal lobe epilepsy. Researchers are not certain if the structural changes cause the functional changes, or vice versa.
"It’s probably a breakdown of myelin, which is the insulation of neurons, causing a slowdown in the propagation of information, but we don’t know for sure," Dr. Stufflebeam said.
Dr. Stufflebeam and colleagues plan to continue their research, using structural and functional MRI with electroencephalography and magnetoencephalography to track diffusion changes and look at real-time brain activity.
"Our long-term goal is to see if we can we predict from diffusion studies who will respond to surgery and who will not," he said.
(Source: eurekalert.org)
Important breakthrough in identifying the effect of epilepsy treatment
50 years after valproate was first discovered, research published today in the journal Neurobiology of Disease, reports how the drug works to block seizure progression.
Valproate (variously labelled worldwide as Epilim, Depacon, Depakene, Depakote, Orlept, Episenta, Orfiril, and Convulex) is one of the world’s most highly prescribed treatments for epilepsy. It was first discovered to be an effective treatment for epilepsy, by accident, in 1963 by a group of French scientists. In thousands of subsequent experiments, animals have been used to investigate how valproate blocks seizures, without success. Scientists from Royal Holloway and University College London have now identified how valproate blocks seizures in the brain, by using a simple amoeba.
“The discovery of how valproate blocks seizures, initially using the social amoeba Dictyostelium, and then replicated using accepted seizure models, highlights the successful use of non-animal testing in biomedical research,” said Professor Robin Williams from the School of Biological Sciences at Royal Holloway.
“Sodium valproate is one of the most effective antiepileptic drugs in many people with epilepsy, but its use has been limited by side-effects, in particular its effect in pregnant women on the unborn child,” said Professor Matthew Walker from the Institute of Neurology at University College London. “Understanding valproate’s mechanism of action is a first step to developing even more effective drugs that lack many of valproate’s side-effects.
“Our study also found that the decrease of a specific chemical in the brain at the start of the seizure causes even more seizure activity. This holds important implications for identifying underlying causes,” added Professor Williams.
(Source: rhul.ac.uk)
Brain Connectivity Can Predict Epilepsy Surgery Outcomes
A discovery from Case Western Reserve and Cleveland Clinic researchers could provide epilepsy patients invaluable advance guidance about their chances to improve symptoms through surgery.
Assistant Professor of Neurosciences Roberto Fernández Galán, PhD, and his collaborators have identified a new, far more accurate way to determine precisely what portions of the brain suffer from the disease. This information can give patients and physicians better information regarding whether temporal lobe surgery will provide the results they seek.
“Our analysis of neuronal activity in the temporal lobe allows us to determine whether it is diseased, and therefore, whether removing it with surgery will be beneficial for the patient,” Galán said, the paper’s senior author. “In terms of accuracy and efficiency, our analysis method is a significant improvement relative to current approaches.”
The findings appear in research published October 30 in the open access journal PLOS ONE.
About one-third of patients with temporal lobe epilepsy do not respond to medical treatment and opt to do lobectomies to alleviate their symptoms. Yet the surgery’s success rate is only 60 to 70 percent because of the difficulties in identifying the diseased brain tissue prior to the procedures.
Galán and investigators from Cleveland Clinic determined that using intracranial electroencephalography (iEEG) to measure patients’ functional neural connectivity – that is, the communication from one brain region to another - identified the epileptic lobe with 87 percent accuracy. An iEEG records electrical activity with electrodes implanted in the brain. Key indicators of a diseased lobe are weak and similar connections.
In the retrospective study, Galán and Arun Antony, MD, formerly a senior clinical fellow in the Epilepsy Center at Cleveland Clinic and now an assistant professor of neurology at the University of Pittsburgh, examined data from 23 patients with temporal lobe epilepsy who had all or part of their temporal lobes removed after iEEG evaluations performed at Cleveland Clinic. The researchers examined the results of patients’ preoperative iEEG to determine the degree of functional connectivity that was associated with successful surgical outcomes.
“The concept of functional connectivity has been extensively studied by basic science researchers, but has not found a way into the realm of clinical epilepsy treatment yet,” Antony said, the paper’s first author. “Our discovery is another step towards the use of measures of functional connectivity in making clinical decisions in the treatment of epilepsy.”
As a standard preoperative test for lobectomy surgery, physicians analyze iEEG traces looking for simultaneous discharges of neurons that appear as spikes in the recordings, which indicate epileptic activity. This PLOS ONE discovery evaluates the data differently by examining normal brain activity in the absence of spikes and inferring connectivity.
(Source: newswise.com)
Gene Found To Foster Synapse Formation In The Brain
Researchers at Johns Hopkins say they have found that a gene already implicated in human speech disorders and epilepsy is also needed for vocalizations and synapse formation in mice. The finding, they say, adds to scientific understanding of how language develops, as well as the way synapses — the connections among brain cells that enable us to think — are formed. A description of their experiments appears in Science Express on Oct. 31.
A group led by Richard Huganir, Ph.D., director of the Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, set out to investigate genes involved in synapse formation. Gek-Ming Sia, Ph.D., a research associate in Huganir’s laboratory, first screened hundreds of human genes for their effects on lab-grown mouse brain cells. When one gene, SRPX2, was turned up higher than normal, it caused the brain cells to erupt with new synapses, Sia found.
When Huganir’s team injected fetal mice with an SRPX2-blocking compound, the mice showed fewer synapses than normal mice even as adults, the researchers found. In addition, when SRPX2-deficient mouse pups were separated from their mothers, they did not emit high-pitched distress calls as other pups do, indicating they lacked the rodent equivalent of early language ability.
Other researchers’ analyses of the human genome have found that mutations in SRPX2 are associated with language disorders and epilepsy, and when Huganir’s team injected the human SRPX2 with the same mutations into the fetal mice, they also had deficits in their vocalization as young pups.
Another research group at Institut de Neurobiologie de la Méditerranée in France had previously shown that SRPX2 interacts with FoxP2, a gene that has gained wide attention for its apparently crucial role in language ability.
Huganir’s team confirmed this, showing that FoxP2 controls how much protein the SRPX2 gene makes and may affect language in this way. “FoxP2 is famous for its role in language, but it’s actually involved in other functions as well,” Huganir comments. “SRPX2 appears to be more specialized to language ability.” Huganir suspects that the gene may also be involved in autism, since autistic patients often have language impairments, and the condition has been linked to defects in synapse formation.
This study is only the beginning of teasing out how SRPX2 acts on the brain, Sia says. “We’d like to find out what other proteins it acts on, and how exactly it regulates synapses and enables language development.”
From football to flies: lessons about traumatic brain injury
Faced with news of suicides and brain damage in former professional football players, geneticist Barry Ganetzky bemoaned the lack of model systems for studying the insidious and often delayed consequences linked to head injuries.
Then he remembered an unexplored observation from nearly 40 years ago: a sharp strike to a vial of fruit flies left them temporarily stunned, only to recover a short time later. At the time he had marked it only as a curiosity.
Now a professor of genetics at UW–Madison, Ganetzky is turning his accidental discovery into a way to study traumatic brain injury (TBI). He and David Wassarman, a UW professor of cell and regenerative biology, report this week (Oct. 14) in the Proceedings of the National Academy of Sciences on the first glimpses of the genetic underpinnings of susceptibility to brain injuries and links to human TBI.
TBIs occur when a force on the body jostles the brain inside the head, causing it to strike the inside of the skull. More than 1.7 million TBIs occur each year in the United States, about one-third due to falls and the rest mainly caused by car crashes, workplace accidents, and sports injuries. TBIs are also a growing issue in combat veterans exposed to explosions.
In many cases, the immediate effects of TBI are temporary and may seem mild — confusion, dizziness or loss of coordination, headaches, vision problems. But over time, impacts may lead to neurodegeneration and related symptoms, including memory loss, cognitive problems, severe depression, or Alzheimer’s-like dementia. Together TBIs cost tens of billions of dollars annually in medical expenses and indirect costs such as lost productivity.
Though TBIs can be classified from “mild” to “severe” based on symptoms, there is a poor understanding of the underlying medical causes.
“Unlike many important medical problems — high blood pressure, cancer, diabetes, heart disease — where we know something about the biology, we know almost nothing about TBI,” Ganetzky says. “Why does a blow to the head cause epilepsy? Or how does it lead down the road to neurodegeneration? Nobody has answers to those questions — in part, because it’s really hard to study in humans.”
Enter the fruit fly. The fly brain is encased in a hard cuticle analogous to the skull, and the basic mechanisms affecting nervous system function are the same in flies and mammals. In the new study, Ganetzky and Wassarman describe a way to reproducibly inflict traumas that seem to mimic the injuries and symptoms of human TBI.
“Now we have a system where we can look at the variables that are the inputs into TBI and determine the relative contributions of each to the pathological outcomes. That’s the real power of the flies,” says Wassarman.
As with humans, few flies die from the immediate impact. Afterward, though, the treated flies show many of the same physical consequences as humans who sustain concussions or other TBIs, including temporary incapacitation, loss of coordination and activation of the innate immune response in the short term, followed by neurodegeneration and sometimes an early death.
The researchers, led by Rebeccah Katzenberger, senior research specialist in the UW Department of Cell and Regnerative Biology, also found that age seems to play an important role. Older flies are more susceptible than younger ones to the effects of the impact and, Wassarman says, many of the outcomes of TBI are very similar to normal aging processes.
With this model, the researchers say, they can now draw on the vast collection of genetic tools and techniques available for fruit flies to probe the underlying drivers of damage.
“What we really want is to understand the immediate and long term consequences in cellular and molecular terms,” says Ganetzky. “From that understanding we can proceed in a more directed way to diagnostics and therapeutics.”
One of the key things they have already identified is the crucial role genetics plays in determining the outcome of an injury, revealed by the high degree of variability seen among different strains of flies. This finding may explain why all potential TBI drugs to date have failed in clinical trials despite showing promise in individual rodent models.
As Wassarman explains, “The heart of the problem of solving traumatic brain injury is that we’re all different.”
They are continuing to develop the model through large-scale genetic analysis and have already found that different sets of genes correlate with susceptibility in flies of different ages. With their system, they can also examine the effects of repeated injuries.
Ganetzky sees tremendous potential for developing applications from the fly-based approach and the Wisconsin Alumni Research Foundation (WARF) has filed for patent protection on the discovery.
“These exciting findings that we can study traumatic brain injury — a disorder of growing concern for athletes, the military, and parents — in the elegantly simple model of fruit flies is sure to interest those researchers and companies looking to address this concern,” says Jennifer Gottwald, WARF licensing manager. “The use of this model can accelerate the work of the medical research community in finding treatments and therapies to help patients.”
(Source: news.wisc.edu)
Brain study uncovers vital clue in bid to beat epilepsy
People with epilepsy could be helped by new research into the way a key molecule controls brain activity during a seizure.
Researchers have identified the role played by of a protein – called BDNF – and say the discovery could lead to new drugs that calm the symptoms of epileptic seizures.
Scientists analysed the way cells communicate when the brain is most active – such as in epileptic seizures – when electrical signalling by the brain’s neurons is increased.
They found that the BDNF molecule – which is known to be released in the brain during seizures – blocks a specific process known as activity-dependent bulk endocytosis (ABDE).
By blocking this process during an epileptic seizure, BDNF increases the release of neurotransmitters and causes heightened electrical activity in the brain.
Since ADBE is only triggered during high brain activity, drugs designed to target this process could have fewer side effects for normal day to day brain function, researchers say.
Experts say that not all epilepsy patients respond to current drug treatments and the finding could lead to the development of new medicines.
The team, however, offered a word of caution. Since ABDE is also implicated in a range of brain functions, such as creating new memories, more research is needed to establish what the effects of manipulating this molecule might be on these key processes.
The study, led by the University of Edinburgh, is published in the journal Nature Communications. The research was funded by the Wellcome Trust and the Medical Research Council.
Dr Mike Cousin, of the University of Edinburgh’s Centre for Integrative Physiology, who led the research, said: “Around one third of people with epilepsy do not respond to the treatments we currently have available. By studying the way brain cells behave during seizures, we have been able to uncover an exciting new research avenue for research into anti-epileptic therapies.”
Researchers will now focus on identifying specific genes that control this brain process to determine whether they hold the key to new drug treatments.
(Source: eurekalert.org)
Scientists fish for new epilepsy model and reel in potential drug
NIH-funded study finds zebrafish model may help identify treatments for a severe form of childhood epilepsy
According to new research on epilepsy, zebrafish have certainly earned their stripes. Results of a study in Nature Communications suggest that zebrafish carrying a specific mutation may help researchers discover treatments for Dravet syndrome (DS), a severe form of pediatric epilepsy that results in drug-resistant seizures and developmental delays.
Scott C. Baraban, Ph.D., and his colleagues at the University of California, San Francisco (UCSF), carefully assessed whether the mutated zebrafish could serve as a model for DS, and then developed a new screening method to quickly identify potential treatments for DS using these fish. This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health and builds on pioneering epilepsy zebrafish models first described by the Baraban laboratory in 2005.
Dravet syndrome is commonly caused by a mutation in the Scn1a gene, which encodes for Nav1.1, a specific sodium ion channel found in the brain. Sodium ion channels are critical for communication between brain cells and proper brain functioning.
The researchers found that the zebrafish that were engineered to have the Scn1a mutation that causes DS in humans exhibited some of the same characteristics, such as spontaneous seizures, commonly seen in children with DS. Unprovoked seizure activity in the mutant fish resulted in hyperactivity and whole-body convulsions associated with very fast swimming. These types of behaviors are not seen in normal healthy zebrafish.
“We were also surprised at how similar the mutant zebrafish drug profile was to that of Dravet patients,” said Dr. Baraban. “Antiepileptic drugs shown to have some benefits in patients (such as benzodiazepines or stiripentol) also exhibited some antiepileptic activity in these mutants. Conversely, many of the antiepileptic drugs that do not reduce seizures in these patients showed no effect in the mutant zebrafish.”
In this study, the researchers developed a fast and automated drug screen to quickly test the effectiveness of various compounds in mutant zebrafish. The researchers tracked behavior and measured brain activity in the mutant zebrafish to determine if the compounds had an impact on seizures.
“Scn1a mutants seize often, so it is relatively easy to monitor their seizure behavior at baseline and then again after a drug application,” said Dr. Baraban. “Using zebrafish placed individually in a 96-part petri dish we can accurately quantify this seizure behavior. In this way, we can test almost 100 fish at one time and quickly determine whether a drug candidate has any effect on these spontaneous seizures.”
In the first such application of this approach, UCSF researchers screened 320 compounds and found that clemizole was most effective in inhibiting seizure activity. Clemizole is approved by the U.S. Food and Drug Administration and has a safe toxicology profile. “This finding was completely unexpected. Based on what is currently known about clemizole, we did not predict that it would have antiepileptic effects,” said Dr. Baraban.
These findings suggest that Scn1a mutant zebrafish may serve as a good model of DS and that the drug screen may be effective in quickly identifying novel therapies for epilepsy.
Dr. Baraban also noted that someday these experiments can be “personalized,” by looking at mutated zebrafish that use genetic information from individual patients.
(Source: ninds.nih.gov)