Posts tagged epilepsy
Articles and news from the latest research reports.
(Image caption: Calcium imaging of neurons in a rat hippocampal slice through transparent graphene electrode. Black square at the center is transparent graphene electrode and neurons are shown in green. Yellow traces shows a representative example of electrophysiological recordings with graphene electrode. Credit: Hajime Takano and Duygu Kuzum)
Researchers from the Perelman School of Medicine and School of Engineering at the University of Pennsylvania and The Children’s Hospital of Philadelphia have used graphene — a two-dimensional form of carbon only one atom thick — to fabricate a new type of microelectrode that solves a major problem for investigators looking to understand the intricate circuitry of the brain.
Pinning down the details of how individual neural circuits operate in epilepsy and other neurological disorders requires real-time observation of their locations, firing patterns, and other factors, using high-resolution optical imaging and electrophysiological recording. But traditional metallic microelectrodes are opaque and block the clinician’s view and create shadows that can obscure important details. In the past, researchers could obtain either high-resolution optical images or electrophysiological data, but not both at the same time.
The Center for NeuroEngineering and Therapeutics (CNT), under the leadership of senior author Brian Litt, PhD, has solved this problem with the development of a completely transparent graphene microelectrode that allows for simultaneous optical imaging and electrophysiological recordings of neural circuits. Their work was published this week in Nature Communications.
"There are technologies that can give very high spatial resolution such as calcium imaging; there are technologies that can give high temporal resolution, such as electrophysiology, but there’s no single technology that can provide both," says study co-first-author Duygu Kuzum, PhD. Along with co-author Hajime Takano, PhD, and their colleagues, Kuzum notes that the team developed a neuroelectrode technology based on graphene to achieve high spatial and temporal resolution simultaneously.
Aside from the obvious benefits of its transparency, graphene offers other advantages: “It can act as an anti-corrosive for metal surfaces to eliminate all corrosive electrochemical reactions in tissues,” Kuzum says. “It’s also inherently a low-noise material, which is important in neural recording because we try to get a high signal-to-noise ratio.”
While previous efforts have been made to construct transparent electrodes using indium tin oxide, they are expensive and highly brittle, making that substance ill-suited for microelectrode arrays. “Another advantage of graphene is that it’s flexible, so we can make very thin, flexible electrodes that can hug the neural tissue,” Kuzum notes.
In the study, Litt, Kuzum, and their colleagues performed calcium imaging of hippocampal slices in a rat model with both confocal and two-photon microscopy, while also conducting electrophysiological recordings. On an individual cell level, they were able to observe temporal details of seizures and seizure-like activity with very high resolution. The team also notes that the single-electrode techniques used in the Nature Communications study could be easily adapted to study other larger areas of the brain with more expansive arrays.
The graphene microelectrodes developed could have wider application. “They can be used in any application that we need to record electrical signals, such as cardiac pacemakers or peripheral nervous system stimulators,” says Kuzum. Because of graphene’s nonmagnetic and anti-corrosive properties, these probes “can also be a very promising technology to increase the longevity of neural implants.” Graphene’s nonmagnetic characteristics also allow for safe, artifact-free MRI reading, unlike metallic implants.
Kuzum emphasizes that the transparent graphene microelectrode technology was achieved through an interdisciplinary effort of CNT and the departments of Neuroscience, Pediatrics, and Materials Science at Penn and the division of Neurology at CHOP.
Ertugrul Cubukcu’s lab at Materials Science and Engineering Department helped with the graphene processing technology used in fabricating flexible transparent neural electrodes, as well as performing optical and materials characterization in collaboration with Euijae Shim and Jason Reed. The simultaneous imaging and recording experiments involving calcium imaging with confocal and two photon microscopy was performed at Douglas Coulter‘s Lab at CHOP with Hajime Takano. In vivo recording experiments were performed in collaboration with Halvor Juul in Marc Dichter’s Lab. Somatosensory stimulation response experiments were done in collaboration with Timothy Lucas’s Lab, Julius De Vries, and Andrew Richardson.
As the technology is further developed and used, Kuzum and her colleagues expect to gain greater insight into how the physiology of the brain can go awry. “It can provide information on neural circuits, which wasn’t available before, because we didn’t have the technology to probe them,” she says. That information may include the identification of specific marker waveforms of brain electrical activity that can be mapped spatially and temporally to individual neural circuits. “We can also look at other neurological disorders and try to understand the correlation between different neural circuits using this technique,” she says.
Brain surgery through the cheek
For those most severely affected, treating epilepsy means drilling through the skull deep into the brain to destroy the small area where the seizures originate – invasive, dangerous and with a long recovery period.
Five years ago, a team of Vanderbilt engineers wondered: Is it possible to address epileptic seizures in a less invasive way? They decided it would be possible. Because the area of the brain involved is the hippocampus, which is located at the bottom of the brain, they could develop a robotic device that pokes through the cheek and enters the brain from underneath which avoids having to drill through the skull and is much closer to the target area.
To do so, however, meant developing a shape-memory alloy needle that can be precisely steered along a curving path and a robotic platform that can operate inside the powerful magnetic field created by an MRI scanner.
The engineers have developed a working prototype, which was unveiled in a live demonstration this week at the Fluid Power Innovation and Research Conference in Nashville by David Comber, the graduate student in mechanical engineering who did much of the design work.
The business end of the device is a 1.14 mm nickel-titanium needle that operates like a mechanical pencil, with concentric tubes, some of which are curved, that allow the tip to follow a curved path into the brain. (Unlike many common metals, nickel-titanium is compatible with MRIs). Using compressed air, a robotic platform controllably steers and advances the needle segments a millimeter at a time.
According to Comber, they have measured the accuracy of the system in the lab and found that it is better than 1.18 mm, which is considered sufficient for such an operation. In addition, the needle is inserted in tiny, millimeter steps so the surgeon can track its position by taking successive MRI scans.
According to Associate Professor of Mechanical Engineering Eric Barth, who headed the project, the next stage in the surgical robot’s development is testing it with cadavers. He estimates it could be in operating rooms within the next decade.
To come up with the design, the team began with capabilities that they already had.
“I’ve done a lot of work in my career on the control of pneumatic systems,” Barth said. “We knew we had this ability to have a robot in the MRI scanner, doing something in a way that other robots could not. Then we thought, ‘What can we do that would have the highest impact?’”
At the same time, Associate Professor of Mechanical Engineering Robert Webster had developed a system of steerable surgical needles. “The idea for this came about when Eric and I were talking in the hallway one day and we figured that his expertise in pneumatics was perfect for the MRI environment and could be combined with the steerable needles I’d been working on,” said Webster.
The engineers identified epilepsy surgery as an ideal, high-impact application through discussions with Associate Professor of Neurological Surgery Joseph Neimat. They learned that currently neuroscientists use the through-the-cheek approach to implant electrodes in the brain to track brain activity and identify the location where the epileptic fits originate. But the straight needles they use can’t reach the source region, so they must drill through the skull and insert the needle used to destroy the misbehaving neurons through the top of the head.
Comber and Barth shadowed Neimat through brain surgeries to understand how their device would work in practice.
“The systems we have now that let us introduce probes into the brain – they deal with straight lines and are only manually guided,” Neimat said. “To have a system with a curved needle and unlimited access would make surgeries minimally invasive. We could do a dramatic surgery with nothing more than a needle stick to the cheek.”
The engineers have designed the system so that much of it can be made using 3-D printing in order to keep the price low. This was achieved by collaborating with Jonathon Slightam and Vito Gervasi at the Milwaukee School of Engineering who specialize in novel applications for additive manufacturing.
Protein pairing builds brain networks
Neural networks are formed by the interconnection of specific neurons in the brain. The molecular mechanisms involved in creating these connections, however, have so far eluded scientists. Research led by Jun Aruga from the RIKEN Brain Science Institute has now identified an interaction between two proteins that is crucial for making connections between specific types of neurons, with implications for some neurological disorders.
Connections between neurons are made via synapses—small gaps across which chemicals called neurotransmitters pass, relaying signals from a presynaptic neuron to a postsynaptic neuron. Aruga and his colleagues focused on a protein called mGluR7, which is found only at synapses with a specific type of postsynaptic neuron in an area of the brain involved in forming memories.
“mGluR7 is located on the presynaptic side of connections made with hippocampal local inhibitory neurons,” explains Aruga. “Previous studies have proposed that this protein prevents neurotransmitter release from the presynaptic neuron when the neurotransmitter glutamate binds to it.”
The researchers discovered that the localization of mGluR7 to specific synapses is determined by the presence of another protein called Elfn1. This protein is found on the other side of the same synapses, directly opposite mGluR7. When the researchers artificially introduced Elfn1 into cultured cells, mGluR7 became associated with the same cells, and they showed that this was due to a physical interaction between the two proteins. Conversely, deleting Elfn1 in the brains of mice reduced the amount of mGluR7 at the synapses.
These changes interfered with the process of strengthening connections at synapses, which takes place during memory formation, and caused patterns of brain waves that indicated abnormally high levels of electrical activity. Genetically altered mice also exhibited other symptoms that resembled human conditions.
“Deleting Elfn1 increased the susceptibility of mice to seizures,” explains Aruga. “It also enhanced behaviors similar to attention deficit hyperactivity disorder (ADHD).”
Indeed, the researchers found that humans with epilepsy and ADHD also had a faulty version of the gene encoding Elfn1, suggesting that a deficit in the ability of Elfn1 to localize mGluR7 and form specific connections in neural networks is important in some neurological conditions.
“In combination, the human and mouse results implicate the Elfn1–mGluR7 complex in the pathophysiology of epilepsy and ADHD, at least in part,” explains Aruga, although he remains cautious at this early stage of research. “Because of sample size limitations, the human genetics result is not conclusive, but we are now awaiting the results of follow-up studies with additional subjects.”
You Don’t Walk Alone
Breakthrough in detecting early onset of refractory epilepsy in children will lead to effective treatment using non-pharmacological therapies.
65 million people around the world today suffer from epilepsy, a condition of the brain that may trigger an uncontrollable seizure at any time, often for no known reason. A seizure is a disruption of the electrical communication between neurons, and someone is said to have epilepsy if they experience two or more unprovoked seizures separated by at least 24 hours.
Epilepsy is the most common chronic disease in pediatric neurology, with about 0.5-1% of children developing epilepsy during their lifetime. A further 30-40% of epileptic children develop refractory epilepsy, a particular type of epilepsy that cannot be managed by antiepileptic drugs (AED). Regardless of etiology, children with refractory epilepsy are invariably exposed to a variety of physical, psychological and social morbidities. Patients whose seizures are difficult to control could benefit from non-pharmacological therapies, including surgery, deep brain stimulation and ketogenic diets. Therefore, the early identification of patients whose seizures are refractory to AED would allow them to receive alternative therapies at an appropriate time.
Despite idiopathic etiology being a significant predictor of a lower risk of refractory epilepsy, a subset of patients with idiopathic epilepsy might still be refractory to medical treatment.
Using a new electroencephalography (EEG) analytical method, a team of medical doctors and scientists in Taiwan has successfully developed a tool to detect certain EEG features often present in children with idiopathic epilepsy.
The team developed an efficient, automated and quantitative approach towards the early prediction of refractory idiopathic epilepsy based on EEG classification analysis. EEG analysis is widely employed to investigate brain disorders and to study brain electrical activity. In the study, a set of artifact-free EEG segments was acquired from the EEG recordings of patients belonging to two classes of epilepsy: well-controlled and refractory. To search for significantly discriminative EEG features and to reduce computational costs, a statistical approach involving global parametric features was adopted across EEG channels as well as over time. A gain ratio-based feature selection was then performed.
The study found a significantly higher DecorrTime avg AVG and RelPowDelta avg AVG in the well-controlled group than in the refractory group. This suggests that refractory patients have a higher risk of seizure attacks than well-controlled patients.
The main contributions of this study are as follows:
- the generalisation of 10 significant EEG features into a concept for the recognition and identification of potential refractory epilepsy in patients with idiopathic epilepsy, based on EEG classification analysis;
- the development of a diagnostic tool based conceptually on these 10 EEG features, using a support vector machine (SVM) classification model to discriminate between well-controlled idiopathic epilepsy and refractory idiopathic epilepsy, which will facilitate subsequent expert visual EEG interpretation.
Further research with more diversity (in terms of pediatric and adult participants) is encouraged to expand on the tool’s reliability and generalisation. This study was supported partly by a grant from the Kaohsiung Medical University Hospital and grants from Ministry of Science and Technology, Taiwan.
The paper can be found in the upcoming issue of the International Journal of Neural Systems (IJNS)
Seizures and sudden death: When SUMO ‘wrestles’ potassium channels
A gene crucial for brain and heart development may also be associated with sudden unexplained death in epilepsy (SUDEP), the most common cause of early mortality in epilepsy patients.
Scientists at The University of Texas MD Anderson Cancer Center have created a new animal model for SUDEP and have shown that mice who have a partial deficiency of the gene SENP2 (Sentrin/SUMO-specific protease 2) are more likely to develop spontaneous seizures and sudden death. The finding occurred when observing mice originally bred for studying a link between SENP2 deficiency and cancer.
"SENP2 is highly present in the hippocampus, a critical brain region for seizure genesis," said Edward Yeh, M.D., chair of cardiology at MD Anderson. "Understanding the genetic basis for SUDEP is crucial given that the rate of sudden death in epilepsy patients is 20-fold that of the general population, with SUDEP the most common epilepsy-related cause of death."
Yeh’s findings were published in this month’s issue of Neuron.
Although it’s not yet known what causes SUDEP in humans, inactivation of potassium channels genes have been linked to SUDEP in animal models. Potassium channels are found in most cell types and control a large variety of cell functions.
"These animal models demonstrated an important connection between the brain and heart. However, it remains unclear whether seizure and sudden death are two separate manifestations of potassium channel deficiency in the brain and the heart, or whether seizures predispose the heart to lethal cardiac arrhythmia," said Yeh.
The study revealed that when SENP2 was deficient in the brain, seizures activated a part of the nervous system responsible for regulating the heart’s electrical system. This resulted in a phenomenon known as atrioventricular conduction block, which effectively slowed down and then stopped the heart.
Yeh’s team observed that the SENP2-deficient mice appeared normal at birth, but by 6 to 8 weeks, experienced convulsive seizures, and then sudden death. He believes the reason may lie with protein modifiers called SUMO. SENP2 deficiency results in a process known as hyper-SUMOylation, which dramatically impacts potassium channels in the brain.
"One of the channels, Kv7, is significantly diminished or ‘closed’ due to the lack of SENP2," said Yeh. "In mice this led to seizures and cardiac arrest."
In humans, the good news is that an FDA-approved drug, retigabine works by “opening” the Kv7 channel. The therapy was developed for treating partial-onset seizures. The findings in Yeh’s new mouse model clearly demonstrate a previously unknown cause of SUDEP, which may open up new opportunities for study and treatment in the future.
(Source: eurekalert.org)
Mouse model for epilepsy, Alzheimer’s gives window into the working brain
University of Utah scientists have developed a genetically engineered line of mice that is expected to open the door to new research on epilepsy, Alzheimer’s and other diseases.
The mice carry a protein marker, which changes in degree of fluorescence in response to different calcium levels. This will allow many cell types, including cells called astrocytes and microglia, to be studied in a new way.
"This is opening up the possibility to decipher how the brain works," said Petr Tvrdik, Ph.D., a research fellow in human genetics and a senior author on the study.
The research was published Aug. 14, 2014, in Neuron, a world-leading neuroscience journal. The work is the result of a three-year study involving multiple labs connected with The Brain Institute at the University of Utah. The lead author is J. Michael Gee, who is pursuing both a medical degree and a graduate degree in bioengineering at the university.
"We’re really in the era of team science," said John White, Ph.D., professor of bioengineering, executive director of the Brain Institute and the study’s corresponding author.
With the new mouse line, scientists can use a laser-based fluorescence microscope to study the calcium indicator in the glial cells of the living mouse, either when the mouse is anesthetized or awake. Calcium is studied because it is an important signaling molecule in the body and it can reveal how well the brain is functioning.
Using this method, the scientists are essentially creating a window into the working brain to study the interactions between neurons, astrocytes and microglia.
"We believe this will give us new insights for treatments of epilepsy and for new views of how the immune system of the brain works," White said.
About one-third of the 3 million Americans estimated to have epilepsy lack adequate treatment to manage the disease.
Describing a long-standing collaboration with fellow university researcher and professor of pharmacology and toxicology Karen Wilcox, Ph.D., White said, “We believe the glial cells are malfunctioning in epilepsy. What we’re trying to do is find out in what ways astrocytes participate in the disease.”
This research is expected to lead to new classes of drugs.
The ability to track calcium changes in microglial cells will also open up the possibility of studying inflammatory diseases of the brain. Every neurological disease, including Multiple Sclerosis and Alzheimer’s, appears to include components of inflammation, the scientists said.
"Live imaging and monitoring microglial activity and responses to inflammation was not possible before," said Tvrdik, particularly in living animals. In the past, researchers studied post-mortem tissue or relied on invasive approaches using synthetic dyes.
(Source: eurekalert.org)
Reduction of tau protein improves symptoms in model of severe childhood epilepsy
Researchers at the Gladstone Institutes have shown that reducing brain levels of the protein tau effectively blocks the development of disease in a mouse model of Dravet syndrome, a severe intractable form of childhood epilepsy. This therapeutic strategy not only suppressed seizure activity and premature death, but also improved cognitive and behavioral abnormalities that can accompany this syndrome.
Previous studies from this group have shown that lowering tau levels reduces abnormal brain activity in models of Alzheimer’s disease, but this is the first demonstration that tau reduction may also be beneficial in intractable genetic epilepsy.
"It would really be wonderful if tau reduction turned out to be useful not only in Alzheimer’s disease, but also in other disabling neurological conditions for which there currently are no effective treatments," said senior author Lennart Mucke, MD, the director of the Gladstone Institute of Neurological Disease and a professor of Neurology and Neuroscience at the University of California, San Francisco. "We suspected that this approach might be beneficial in Dravet, but we couldn’t be sure because of the severity of this syndrome and the corresponding model. We are thrilled that our strategy was so effective, but a lot more work is needed to advance it into the clinic."
Dravet syndrome is one of the most challenging forms of childhood epilepsy, resulting from a specific genetic mutation that affects sodium channels in the brain. Frequent, relentless seizures are accompanied by cognitive impairments and behavioral problems similar to autism, and up to 20% of patients succumb to sudden death. Current treatments for Dravet syndrome are largely ineffective, making research into the disorder particularly urgent.
"I am especially excited about the improvements we observed in cognitive and behavioral dysfunctions because these abnormalities are particularly hard on the kids—and their parents," said first author Ania Gheyara, MD, PhD, a staff scientist at Gladstone who is also affiliated with the UCSF Department of Pathology. "Our hope is that this approach will be broadly applicable to many different types of epilepsy."
In the study, which was published online today in the Annals of Neurology, the scientists reduced the level of the protein tau by genetically engineering Dravet mouse models, “knocking out” the gene associated with tau production. The deletion of one copy of the gene resulted in substantial improvements in most symptoms, while deleting both copies eliminated them almost completely. This included a significant reduction in both spontaneous and heat-induced seizures. The latter were used to mimic the fever-related seizures that are often seen in the early stages of Dravet syndrome. Network activity in the brain was also normalized, providing additional support for the remarkable ability of tau reduction to suppress epileptic activity.
Additionally, tau reduction ameliorated the learning and memory deficits and behavioral abnormalities present in the Dravet mice, which may relate to the cognitive impairments and autism-like behaviors seen in the human condition.
"The next steps are to develop tau-lowering therapeutics that could be used in humans and to evaluate their safety and efficacy in preclinical studies," said Dr. Mucke, "objectives we are pursuing actively."
(Source: eurekalert.org)
Could your brain be reprogrammed to work better?
Researchers from The University of Western Australia have shown that electromagnetic stimulation can alter brain organisation which may make your brain work better.
In results from a study published today in the prestigious Journal of Neuroscience, researchers from The University of Western Australia and the Université Pierre et Marie Curie in France demonstrated that weak sequential electromagnetic pulses (repetitive transcranial magnetic stimulation - or rTMS) on mice can shift abnormal neural connections to more normal locations.
The discovery has important implications for treatment of many nervous system disorders related to abnormal brain organisation such as depression, epilepsy and tinnitus.
To better understand what magnetic stimulation does to the brain Research Associate Professor Jennifer Rodger from UWA’s School of Animal Biology and her colleagues tested a low-intensity version of the therapy - known as low-intensity repetitive transcranial magnetic stimulation (LI-rTMS) - on mice born with abnormal brain organisation.
Lead author, PhD candidate Kalina Makowiecki, said the research demonstrated that even at low intensities, pulsed magnetic stimulation could reduce abnormally located neural connections, shifting them towards their correct locations in the brain.
"This reorganisation is associated with changes in a specific brain chemical, and occurred in several brain regions, across a whole network. Importantly, this structural reorganisation was not seen in the healthy brain or the appropriate connections in the abnormal mice, suggesting that the therapy could have minimal side effects in humans.
"Our findings greatly increase our understanding of the specific cellular and molecular events that occur in the brain during this therapy and have implications for how best to use it in humans to treat disease and improve brain function," Ms Makowiecki said.
(Source: news.uwa.edu.au)
New research links anxiety to epilepsy-like seizures
New research by clinical psychologists from Arizona State University and the United Kingdom has revealed seizures that could be mistaken for epilepsy are linked to feelings of anxiety.
The team of researchers devised a new set of tests to determine whether there was a link between how people interpret and respond to anxiety, and incidences of psychogenic nonepileptic seizures (PNES).
Nicole Roberts, an associate professor in ASU’s New College of Interdisciplinary Arts and Sciences, collaborated with colleagues from the University of Lincoln, University of Nottingham and University of Sheffield in the United Kingdom. The team’s findings were published in the journal Epilepsy and Behavior.
The researchers used a series of questionnaires and computer tests to determine if a patient regularly avoids situations which might bring on anxiety.
These tests correctly predicted whether a patient had epilepsy or PNES – seizures that can be brought on by threatening situations, sensations, emotions, thoughts or memories – in 83 percent of study participants. Such seizures appear on the surface to be similar to epileptic fits, which are caused by abnormal brain activity.
“This research underscores the fact that PNES is a ‘real’ and disabling disorder with a potentially identifiable pathophysiology,” said Roberts, who directs New College’s Emotion, Culture, and Psychophysiology Laboratory, located on ASU’s West campus. “We need to continue to search for answers, not just in epilepsy clinics, but also in the realm of affective science and complex brain-behavior relationships.”
“PNES can be a very disabling condition, and it is important that we understand the triggers so that we provide the correct care and treatment,” said Lian Dimaro, a clinical psychologist based at Nottinghamshire Healthcare NHS Trust, who served as lead researcher for the study.
“This study was one of the first to bring modern psychological tools of investigation to this problem,” Dimaro said. “The findings support the idea that increasing a person’s tolerance of unpleasant emotions and reducing avoidant behavior may help with treatment, suggesting that patients could benefit from a range of therapies, including acceptance and commitment therapy to help reduce the frequency of seizures, although more research is needed in this area.”
Participants completed questionnaires to determine the level to which they suffered from anxiety, their awareness of their experiences and if they would avoid situations which would make them feel anxious.
They then completed a computer task which required rapid responses to true or false statements. This test was designed to gather data on immediate, or implicit, beliefs about anxiety. Participants also answered questions about common physical complaints that may have no medical explanation, also called somatic symptoms. These can include things like gastrointestinal problems, tiredness and back pain.
Results showed that those with PNES reported significantly more somatic symptoms than others in the study, as well as avoidance of situations which might make them anxious. The group with PNES also scored significantly higher on a measure of how aware they were of their anxiety compared with the control group.
The test subjects were 30 adults with PNES, 25 with epilepsy and 31 with no reported history of seizures who served as a nonclinical control group.
The researchers suggest that including tests to determine levels of anxiety and avoidance behavior may enable health professionals to make earlier diagnosis, and develop more effective intervention plans.
“Epileptic seizures are caused by abnormal electrical activity in the brain, while most PNES are thought to be a consequence of complex psychological processes that manifest in physical attacks,” said David Dawson, a research clinical psychologist from the University of Lincoln.
“It is believed that people suffering with PNES may have difficulty actively engaging with anxiety – a coping style known as experiential avoidance,” Dawson said. “We wanted to examine whether it was possible to make a clear link between seizure frequency and how people experience and manage anxiety. Our study is another step in understanding PNES, which could ultimately lead to better treatment and, therefore, patient outcomes in the future.”
Roberts, who received her doctorate in clinical psychology from the University of California, Berkeley, focuses her research on the study of emotion and on the cultural and biological forces that shape emotional responses. Examples include investigating how ethnicity and culture influence emotional displays and experiences; how the daily hassles of life, such as job stress and sleep deprivation, impact emotion regulation among individuals and couples; and how the emotion system breaks down in patients with psychopathology (such as PNES and post-traumatic stress disorder) or neurological dysfunction (such as epilepsy).
(Source: asunews.asu.edu)
Study finds potential genetic link between epilepsy and neurodegenerative disorders
A recent scientific discovery showed that mutations in prickle genes cause epilepsy, which in humans is a brain disorder characterized by repeated seizures over time. However, the mechanism responsible for generating prickle-associated seizures was unknown.
A new University of Iowa study, published online July 14 in the Proceedings of the National Academy of Sciences, reveals a novel pathway in the pathophysiology of epilepsy. UI researchers have identified the basic cellular mechanism that goes awry in prickle mutant flies, leading to the epilepsy-like seizures.
“This is to our knowledge the first direct genetic evidence demonstrating that mutations in the fly version of a known human epilepsy gene produce seizures through altered vesicle transport,” says John Manak, senior author and associate professor of biology in the College of Liberal Arts and Sciences and pediatrics in the Carver College of Medicine.
Seizure suppression in flies
A neuron has an axon (nerve fiber) that projects from the cell body to different neurons, muscles, and glands. Information is transmitted along the axon to help a neuron function properly.
Manak and his fellow researchers show that seizure-prone prickle mutant flies have behavioral defects (such as uncoordinated gait) and electrophysiological defects (problems in the electrical properties of biological cells) similar to other fly mutants used to study seizures. The researchers also show that altering the balance of two forms of the prickle gene disrupts neural information flow and causes epilepsy.
Further, they demonstrate that reducing either of two motor proteins responsible for directional movement of vesicles (small organelles within a cell that contain biologically important molecules) along tracks of structural proteins in axons can suppress the seizures.
“The reduction of either of two motor proteins, called Kinesins, fully suppressed the seizures in the prickle mutant flies,” says Manak, faculty member in the Interdisciplinary Graduate Programs in Genetics, Molecular and Cellular Biology, and Health Informatics. “We were able to use two independent assays to show that we could suppress the seizures, effectively ‘curing’ the flies of their epileptic behaviors.”
Genetic link between epilepsy and Alzheimer’s
This new epilepsy pathway was previously shown to be involved in neurodegenerative diseases, including Alzheimer’s and Parkinson’s.
Manak and his colleagues note that two Alzheimer’s-associated proteins, amyloid precursor protein and presenilin, are components of the same vesicle, and mutations in the genes encoding these proteins in flies affect vesicle transport in ways that are strikingly similar to how transport is impacted in prickle mutants.
“We are particularly excited because we may have stumbled upon one of the key genetic links between epilepsy and Alzheimer’s, since both disorders are converging on the same pathway,” Manak says. “This is not such a crazy idea. In fact, Dr. Jeff Noebels, a leading epilepsy researcher, has presented compelling evidence suggesting a link between these disorders. Indeed, patients with inherited forms of Alzheimer’s disease also present with epilepsy, and this has been documented in a number of published studies.”
Manak adds, “If this connection is real, then drugs that have been developed to treat neurodegenerative disorders could potentially be screened for anti-seizure properties, and vice versa.”
Manak’s future research will involve treating seizure-prone flies with such drugs to see if he can suppress their seizures.
(Source: now.uiowa.edu)