Posts tagged seizures
Articles and news from the latest research reports.
Geneticists Find Causes for Severe Childhood Epilepsies
Researchers at the University of Arizona have successfully determined the genetic mutations causing severe epilepsies in seven out of 10 children for whom the cause of the disorder could not be determined clinically or by conventional genetic testing.
Instead of sequencing each gene one at a time, the team used a technique called whole-exome sequencing: Rather than combing through all of the roughly 3 billion base pairs of an individual’s entire genome, whole-exome-sequencing deciphers only actual genes, and nearly all of them simultaneously.
“My initial hope was that we would find something in one out of the 10 children in our study. But a 70 percent success rate is beyond anyone’s imagination,” said study leader Michael Hammer, who is a research scientist in the UA’s Arizona Research Labs Division of Biotechnology and a member of the UA BIO5 Institute.
For Hammer, the research hit very close to home. Just last year, his lab tracked down the mutation that had caused the severe – and ultimately fatal – epilepsy in his teenage daughter.
“I figured, if we could do this for one child, we could do it for others.” Hammer explained. “These are children who have had every test imaginable and tried every possible drug combination, and nobody has figured out where their seizures come from and how to stop them.”
The children who participated in the study, published online in the journal Epilepsia, all suffered from severe seizure disorders, and most of them started having seizures within the first year or two after birth.
Unlike individuals afflicted with epilepsy later in life, many of whom can live normal lives with the right medical oversight and medications, early-onset epilepsy can be devastating. Children often develop other severe complications such as intellectual disability, autism and loss of muscle tone or coordination. Early death is not uncommon.
“Because their seizures are not well controlled, and that firestorm of electrical activity in the brain is bad for brain development, the damage can be extensive,” added Linda Restifo, a professor in the UA department of neurology and a BIO5 member who co-authored the study. “The earlier the seizures start and the more severe and frequent they are, the more likely they are to leave the child with permanent developmental disability.”
“The sooner we can catch problems in children and understand what is causing them, the better the chance we have to try and correct them,” Hammer added.
To identify changes in the DNA that are the most likely cause of the disorders, the team focused on a class of mutations called de novo mutations: “typos” in the DNA sequence that are present only in the child. In order to find such mutations, the study included both parents and their child.
Overall, the team found 15 mutations in nine children, seven of which are known or likely to cause epilepsy. No mutations could be found in one of the children.
“In four of the patients. we found mutations that were already known to be associated with epilepsy,” said Krishna Veeramah, a postdoctoral fellow in Hammer’s group and the study’s first author. “However, three patients had mutations in genes that were not previously associated with epilepsy in humans but presented plausible explanations for the disorder.”
“The fact that we found three genes – in a study involving only 10 subjects – that had never been implicated in epilepsy before suggests that many more genetic defects related to developmental brain disorders remain to be discovered,” Veeramah said.
One of the participants in the study was Ashley Wilhelm, a 14-year-old girl from Phoenix, Ariz., whose seizures started when she was only 5 months old. Her first seizures appeared to be triggered by fever, leading doctors to believe they were just that – a side effect of the fever.
“But she soon began to have more and more seizures, and they would last half an hour or longer,” said her mother, Ann. “We had all sorts of tests done, but the doctors kept saying her brain was normal, and that they didn’t see any reason she’d have those seizures.”
Ashley, whose development has severely suffered as a consequence of the repeated seizures, was enrolled in the study through her neurologist, Dinesh Talwar, who co-authored the paper.
Even though her treatment is unlikely to change with the new information, the family said the results brought “more relief than we can explain.”
“Since insurance wouldn’t pay for the testing, and we couldn’t afford it on our own, we were very grateful we were able to participate in the study,” said Jeff Wilhelm, Ashley’s father. “If such a test could be done much earlier, it would ease the pain for everyone involved. What if our son had decided not to consider having children of his own out of concern they might have the disorder?”
“The results from this study have at last given us a breakthrough,” said the mother of another participating teenager. “We had pursued every possible avenue to understand what might be responsible for his epilepsy – magnetic resonance imaging, CT scans, searches for gross chromosome abnormalities or markers associated with epilepsy – with no success.”
“Although the discovery doesn’t yet give us a treatment, it gives us hope for finding one,” she said. “As more research is done on this mutation, drugs to control our son’s seizures will be identified. If more children with epilepsy can be studied and families with children with similar mutations can organize and share resources, there will be more progress.”
Hammer said the approach is applicable to other conditions in which conventional genetic testing has failed to reveal the cause.
“Our work bridges research and clinical practice,” he added. “We can sequence all the genes in your genome in a matter of days and report it to the patient’s family and the physician. That may make a difference in the treatment and management of the disorder in question.”
Centers with the capabilities to do this kind of analysis are few and far between.
“Other centers that do this kind of work will sequence your genome and tell you where and what the mutation is in the DNA sequence, but it’s not that simple,” Hammer said. “In most cases, we find a mutation in a gene not previously known to cause disease, so we need to perform a follow-up study to find out what that mutation actually does.”
To perform these follow-up studies, the UA team has established collaborations with leading scientists at the UA and at other institutions.
“Right now, the benefit to families is primarily to get answers,” said Restifo. “The long-term goal is to collect this kind of information from more children, which will hopefully lead to new research into medications that improve brain development and function.”
Hammer added: “In the meantime, a molecular diagnosis provides immediate relief to the unnecessary guilt parents might feel for their role in causing their child’s suffering. They want answers, not endless doctors visits and tests with negative results, or to have their hopes raised and dashed over and over.”
Encouraged by the success of their approach so far, Hammer and his colleagues already have bigger plans.
“We hope to involve other clinical areas such as cardiology, immunology, gastroenterology – anything that we can apply molecular diagnostics or clinical genomics to at the UA, we want to explore. We want to make the University the core for clinical diagnostics using new sequencing technologies for at least the entire Southwest.”
UA pediatric geneticist Robert Erickson, another co-author and member of the UA Steele Children’s Research Center added, “these efforts will be very important in the diagnosis of newborns with unusual birth defects.”
Epilepsy Cured in Mice Using Brain Cells
Epilepsy that does not respond to drugs can be halted in adult mice by transplanting a specific type of cell into the brain, UC San Francisco researchers have discovered, raising hope that a similar treatment might work in severe forms of human epilepsy.
UCSF scientists controlled seizures in epileptic mice with a one-time transplantation of medial ganglionic eminence (MGE) cells, which inhibit signaling in overactive nerve circuits, into the hippocampus, a brain region associated with seizures, as well as with learning and memory. Other researchers had previously used different cell types in rodent cell transplantation experiments and failed to stop seizures.
Cell therapy has become an active focus of epilepsy research, in part because current medications, even when effective, only control symptoms and not underlying causes of the disease, according to Scott C. Baraban, PhD, who holds the William K. Bowes Jr. Endowed Chair in Neuroscience Research at UCSF and led the new study. In many types of epilepsy, he said, current drugs have no therapeutic value at all.
“Our results are an encouraging step toward using inhibitory neurons for cell transplantation in adults with severe forms of epilepsy,” Baraban said. “This procedure offers the possibility of controlling seizures and rescuing cognitive deficits in these patients.”
The findings, which are the first ever to report stopping seizures in mouse models of adult human epilepsy, will be published online May 5 in the journal Nature Neuroscience.
During epileptic seizures, extreme muscle contractions and, often, a loss of consciousness can cause seizure sufferers to lose control, fall and sometimes be seriously injured. The unseen malfunction behind these effects is the abnormal firing of many excitatory nerve cells in the brain at the same time.
In the UCSF study, the transplanted inhibitory cells quenched this synchronous, nerve-signaling firestorm, eliminating seizures in half of the treated mice and dramatically reducing the number of spontaneous seizures in the rest. Robert Hunt, PhD, a postdoctoral fellow in the Baraban lab, guided many of the key experiments.
In another encouraging step, UCSF researchers reported May 2 that they found a way to reliably generate human MGE-like cells in the laboratory, and that, when transplanted into healthy mice,the cells similarly spun off functional inhibitory nerve cells. That research can be found online in the journal Cell Stem Cell.
In many forms of epilepsy, loss or malfunction of inhibitory nerve cells within the hippocampus plays a critical role. MGE cells are progenitor cells that form early within the embryo and are capable of generating mature inhibitory nerve cells called interneurons. In the Baraban-led UCSF study, the transplanted MGE cells from mouse embryos migrated and generated interneurons, in effect replacing the cells that fail in epilepsy. The new cells integrated into existing neural circuits in the mice, the researchers found.
“These cells migrate widely and integrate into the adult brain as new inhibitory neurons,” Baraban said. “This is the first report in a mouse model of adult epilepsy in which mice that already were having seizures stopped having seizures after treatment.”
The mouse model of disease that Baraban’s lab team worked with is meant to resemble a severe and typically drug-resistant form of human epilepsy called mesial temporal lobe epilepsy, in which seizures are thought to arise in the hippocampus. In contrast to transplants into the hippocampus, transplants into the amygdala, a brain region involved in memory and emotion, failed to halt seizure activity in this same mouse model, the researcher found.
Temporal lobe epilepsy often develops in adolescence, in some cases long after a seizure episode triggered during early childhood by a high fever. A similar condition in mice can be induced with a chemical exposure, and in addition to seizures, this mouse model shares other pathological features with the human condition, such as loss of cells in the hippocampus, behavioral alterations and impaired problem solving.
In the Nature Neuroscience study, in addition to having fewer seizures, treated mice became less abnormally agitated, less hyperactive, and performed better in water-maze tests.
(Source: newswise.com)
Implanted device predicts oncoming seizures in those with epilepsy
A new device may offer hope to people with epilepsy as the technology could predict the onset of seizures in adults who have the condition and can’t be treated with medication, according to Australian scientists.
The small device is implanted in the brain. Researchers at the University of Melbourne said their proof-of-concept study found that it can successfully detect brain activity that would lead to episodes of seizures.
“Knowing when a seizure might happen could dramatically improve the quality of life and independence of people with epilepsy and potentially allow them to avoid dangerous situations, such as driving or swimming, or to take drugs to stop the seizures before they start,” Dr. Mark Cook said.
“The first thing of this was to give people back some independence. If they know when a seizure is going to happen, they can arrange their lives to be better, make themselves safer, go about work and so on in a much more comfortable and relaxed way.”
His complete findings were published Thursday night in the prestigious journal, Lancet Neurology.
Epilepsy is a physical condition marked by sudden, brief changes in the brain’s functioning.
The unusual activity in the brain causes patients to have recurring, unprovoked seizures.
There is a wide spectrum when identifying a seizure, from convulsions on one end to tuning out for just a few seconds before returning to regular activities.
Device monitors abnormal brain activity in patients
In the study, 15 people with focal epilepsy between the ages of 20 and 62 had the device implanted between the skull and brain surface.
The study participants typically experienced between two and 12 seizures per month. Although most cases of epilepsy can be treated with medication, theirs was not responsive to at least two drug therapies.
The device, developed by Seattle-based company NeuroVista, monitors electrical activity in the brain.
Once abnormal electrical activity is flagged, the device sends a message to a second device implanted under the skin of the chest similar to a pacemaker.
The information then makes its way to a wireless, hand-held device that calculates the likelihood of a seizure.
Three coloured lights – red, white or blue – warn users of the probability of encountering a seizure.
The researchers found that the system was right about “high warning” of seizures more than 65 per cent of the time and in about 11 of the 15 subjects.
Eight of the patients kept the device activated for about four months – the accuracy ranged from 56 to 100 per cent.
However, three patients had serious side effects, with two needing the device to be removed.
Cook said the findings are promising. If they’re replicated in larger, longer studies, the technology could even offer insight into how to prevent seizures using fast-acting drugs or brain stimulation to stifle a seizure.
Epilepsy sends differentiated neurons on the run
The smooth operation of the brain requires a certain robustness to fluctuations in its home within the body. At the same time, its extraordinary power derives from an activity structure poised at criticality. In other words, it is highly responsive to many low-threshold events. When forced beyond its comfort zone in parameter space—its operating temperature, electrolytes, sugars, blood gas or even sensory input— the direct result is seizure, coma, or both. It would appear that anything rendered too hot or cold, too concentrated or scarce, precipitates seizure. In those genetically predisposed, or compromised by head trauma, the seizing tends toward full-blown epilepsy. A group in Hamburg, led by Michael Frotscher has been chipping away at the causes of common form a epilepsy, temporal lobe epilepsy (TLE). Their latest research published in the journal, Cerebral Cortex, takes a closer at differentiated neurons in the dentate gyrus of mouse hippocampus. Once thought to be completely immobilized by virtue of their broadly integrated dendritic trees, these neurons are now shown to become migratory once again in direct response to seizure activity.
Genetic predisposition to seizure can come in the form of ongoing chemical or metabolic imbalance due to defects in enzymes, ion channels or receptors. Alternatively it manifests through direct structural defect as a result of a developmental flaw. In slice preparations, Frotscher looked at a particular form of TLE, where the granule cell layer (GCL) in the dentate gyrus is disrupted. The cells there have either failed to migrate along glial scaffolds into a compact layer with clearly defined margins, or aberrant clumps of cells congregate in the wrong places. Seizures secondary to fever have been known to cause this aberrant migration of granule cells, as has a particular kind of mouse mutant known as the reeler mouse.
The catalog of mouse mutants is expansive; it is a veritable library of hopeless monsters. The reeler mutant, known since 1951, has a unique set of issues wherein cells fail to migrate to the right spots in the cerebellum, cortex, and hippocampus. The protein, reelin was later discovered as one of the causes of this particular phenotype. Reelin is an extracellular matrix protein which initially provides scaffolding for neuron migration, and later a fence to fix neurons in place. In mice with mutated reelin protein, cells in all parts of the hippocampus, not just the dentate gyrus are spread out into a broad and diffuse layer.
By injecting kainate (KA), an excitotoxin that predictably results in seizures, into the dentate gyrus, Frotscher biased the granule cells into entering a phase of bursting activity. With their glutamate receptors fully activated by KA, the granule cells fire rapid volleys of spikes followed by deep depolarization periods. Cells that had been fluorescently labeled with GFP and observed with real time video microscopy were also seen to become motile and dispersed. The normal band of granule cells doubled, or tripled, in thickness. Next, Frostcher looked for a link between this response to KA and the reelin protein. Both reelin mRNA and reelin immunoreactivity were found to be reduced in the dentate granule cells that had been dispersed by KA.
Against this tableau of complex responses to KA, is the fact that adult neurogenesis of dentate granule cells occurs within many mammalian species. A narrowly-defined rostral migratory stream normally delivers fresh cells to both the dentate gyrus and olfactory bulb. Application of BrdU, a marker of newly born cells, labeled microglial and astrocytes near the site of injection, but only a few of the granule cells. As an excitotoxin, KA may be expected to kill at least some cells outright, and cause significant dendritic degeneration in many more. An interesting question to ask, is how does KA induce granule cell dispersion despite the dense interconnections with their neighbors?
During KA induced motility, the nucleus was typically observed to translocate within the cell into one of the dendrites, pulling the soma along with it. This process is believed to involve a myosin-dependant forward flow of actin structural protein within the cell. Outside the cell, changes to the reelin matrix appear to be involved as well. One potential mechanism that has emerged is that reelin induces serine phosporylation of cofilin, an actin-associated protein involved in depolymerization. The authors conclude reelin-induced cofilin phosphorylation controls neuronal migration during development, and prevents abnormal motility in the mature brain.
Undoubtedly many mechanisms are involved in the KA-induced seizure and reelin story. Other cell types in the dentate gyrus need to be looked at in closer detail. For example, how reelin expression is regulated, and which cells manufacture it are current areas of study. It is important as well to differentiate between the causes of seizure, and its consequences. On paper they can be neatly packaged concepts but in the real tissue, and in intact animals, they can be anything but.
(Source: medicalxpress.com)
EEG Identifies Seizures in Hospital Patients
Electroencephalogram (EEG), which measures and records electrical activity in the brain, is a quick and efficient way of determining whether seizures are the cause of altered mental status (AMS) and spells, according to a study by scientists at the UC San Francisco.
The research, which focused on patients who had been given an EEG after being admitted to the hospital for symptoms such as AMS and spells, appears on March 27 in Mayo Clinic Proceedings.
“We have demonstrated a surprisingly high frequency of seizures – more than 7 percent – in a general inpatient population,” said senior investigator John Betjemann, MD, a UCSF assistant professor of neurology. “This tells us that EEG is an underutilized diagnostic tool, and that seizures may be an underappreciated cause of spells and AMS.”
The results are important, he said, because EEG can identify treatable causes of AMS or spells, and because “it can prompt the physician to look for an underlying reason for seizures in persons who did previously have them.”
Seizures are treatable with a number of FDA-approved anticonvulsants, he said, “so patients who are quickly diagnosed can be treated more rapidly and effectively. This may translate to shorter lengths of stay and improved patient outcomes.”
In one of the first studies of its kind, Betjemann and his team analyzed the medical records of 1,048 adults who were admitted to a regular inpatient unit of a tertiary care hospital and who underwent an EEG. They found that 7.4 percent of the patients had a seizure of some kind while being monitored.
“As I tell my patients, seizures come in all different flavors, from a dramatic convulsion to a subtle twitching of the face or hand or finger,” said Betjemann. “There might be no outward manifestation at all, other than that the person seems a little spacey. It’s easily missed by family members and physicians alike, but can be picked up by EEG.”
Another 13.4 percent of patients had epileptiform discharges, which are abnormal patterns that indicate patients are at an increased risk of seizures.
Almost 65 percent of patients had their first seizure within one hour of EEG recording, and 89 percent within six hours.
“This is good news for smaller hospitals that don’t have 24 hour EEG coverage, but that do have a technician on duty during the day,” Betjemann said.
He speculated that lack of 24-hour coverage is a major reason that EEG is not used as an inpatient diagnostic tool as often as it might be. “This paper shows that, fortunately, it’s not necessary. Almost two thirds of patients with seizures can be identified in the first hour, and almost 90 percent in the course of a shift.”
EEGs are easy to obtain, painless and noninvasive, said Betjemann. “The technician applies some paste and electrodes and hooks up the machine. All the patient has to do is rest in bed.”
Betjemann said that the next logical research step would be a prospective study. “We have to start at the beginning, see if patients are altered when they are admitted, and do an EEG in a formal standardized setting. Then we’d want to see how often EEG is changing the management of patients – either starting or stopping medications,” he said. “A patient may be having spells, and an EEG might tell you this is not a seizure, and that it’s important not to treat it with anti-epileptic medications.”
(Image: Rex Features)
Cooling may prevent trauma-induced epilepsy
In the weeks, months and years after a severe head injury, patients often experience epileptic seizures that are difficult to control. A new study in rats suggests that gently cooling the brain after injury may prevent these seizures.
“Traumatic head injury is the leading cause of acquired epilepsy in young adults, and in many cases the seizures can’t be controlled with medication,” says senior author Matthew Smyth, MD, associate professor of neurological surgery and of pediatrics at Washington University School of Medicine in St. Louis. “If we can confirm cooling’s effectiveness in human trials, this approach may give us a safe and relatively simple way to prevent epilepsy in these patients.”
The researchers reported their findings in Annals of Neurology.
Cooling the brain to protect it from injury is not a new concept. Cooling slows down the metabolic activity of nerve cells, and scientists think this may make it easier for brain cells to survive the stresses of an injury.
Doctors currently cool infants whose brains may have had inadequate access to blood or oxygen during birth. They also cool some heart attack patients to reduce peripheral brain damage when the heart stops beating.
Smyth has been exploring the possibility of using cooling to prevent seizures or reduce their severity.
“Warmer brain cells seem to be more electrically active, and that may increase the likelihood of abnormal electrical discharges that can coalesce to form a seizure,” Smyth says. “Cooling should have the opposite effect.”
Smyth and colleagues at the University of Washington and the University of Minnesota test potential therapies in a rat model of brain injury. These rats develop chronic seizures weeks after the injury.
Researchers devised a headset that cools the rat brain. They were originally testing its ability to stop seizures when they noticed that cooling seemed to be not only stopping but also preventing seizures.
Scientists redesigned the study to focus on prevention. Under the new protocols, they put headsets on some of the rats that cooled their brains by less than 4 degrees Fahrenheit. Another group of rats wore headsets that did nothing. Scientists who were unaware of which rats they were observing monitored them for seizures during treatment and after the headsets were removed.
Rats that wore the inactive headset had progressively longer and more severe seizures weeks after the injury, but rats whose brains had been cooled only experienced a few very brief seizures as long as four months after injury.
Brain injury also tends to reduce cell activity at the site of the trauma, but the cooling headsets restored the normal activity levels of these cells.
The study is the first to reduce injury-related seizures without drugs, according to Smyth, who is director of the Pediatric Epilepsy Surgery program at St. Louis Children’s Hospital.
“Our results show that the brain changes that cause this type of epilepsy happen in the days and weeks after injury, not at the moment of injury or when the symptoms of epilepsy begin,” says Smyth. “If clinical trials confirm that cooling has similar effects in humans, it could change the way we treat patients with head injuries, and for the first time reduce the chance of developing epilepsy after brain injury.”
Smyth and his colleagues have been testing cooling devices in humans in the operating room, and are planning a multi-institutional trial of an implanted focal brain cooling device to evaluate the efficacy of cooling on established seizures.
How Neuroscience Will Fight Five Age-Old Afflictions
SEIZURES
A device delivers targeted drugs to calm overactive neurons
For years, large clinical trials have treated people with epilepsy using so-called deep-brain stimulation: surgically implanted electrodes that can detect a seizure and stop it with an electrical jolt. The technology leads to a 69 percent reduction in seizures after five years, according to the latest results.
Tracy Cui, a biomedical engineer at the University of Pittsburgh, hopes to improve upon that statistic. Her group has designed an electrode that would deliver both an electrical pulse and antiseizure medication. “We know where we want to apply the drug,” Cui says, “so you would not need a lot of it.”
To build the device, Cui’s team immersed a metal electrode in a solution containing two key ingredients: a molecule called a monomer and the drug CNQX. Zapping the solution with electricity causes the monomers to link together and form a long chain called a polymer. Because the polymer is positively charged, it attracts the negatively charged CNQX, leaving the engineers with their target product: an electrode coated in a film that’s infused with the drug.
The researchers then placed the electrodes in a petri dish with rat neurons. Another zap of electricity disrupted the electrostatic attraction in the film, causing the polymer to release its pharmacological payload—and nearby cells to quiet their erratic firing patterns. Cui says her team has successfully repeated the experiment in living rats. Next, she’d like to test the electrodes in epileptic rats and then begin the long process of regulatory approval for human use.
The body’s blood-brain barrier protects the organ from everything but the smallest molecules, rendering most drugs ineffective. As a result, this drug-delivery mechanism could treat other brain disorders, Cui says. The electrodes can be loaded with any kind of small drug—like dopamine or painkillers—making it useful for treating Parkinson’s disease, chronic pain, or even drug addiction.
DEMENTIA
Electrode arrays stimulate mental processing
Dementia is one of the most well-known and frustrating brain afflictions. It damages many of the fundamental cognitive functions that make us human: working memory, decision-making, language, and logical reasoning. Alzheimer’s, Huntington’s, and Parkinson’s diseases all lead to dementia, and it’s also sometimes associated with multiple sclerosis, AIDS, and the normal process of aging.
Theodore Berger, a biomedical engineer at the University of Southern California, hopes to help people stave off the symptoms of dementia with a device implanted in the brain’s prefrontal cortex, a region crucial for sophisticated cognition. He and colleagues at Wake Forest Baptist Medical Center tested the device in a study involving five monkeys and a memory game.
First the team implanted an electrode array so that it could record from layers 2/3 and 5 of the prefrontal cortex and stimulate layer 5. The neural signals that jet back and forth between these areas relate to attention and decision-making. The team then trained the monkeys to play a computer game in which they saw a cartoon picture—such as a truck, lion, or paint palette—and had to select the same image from a panel of pictures 90 seconds later.
The scientists initially analyzed the electrical signals sent between the two cortical layers when the monkeys made a correct match. In later experiments, the team caused the array to emit the same signal just before the monkey made its decision. The animals’ accuracy improved by about 10 percent. That effect may be even more profound in an impaired brain. When the monkeys played the same game after receiving a hit of cocaine, their performance dropped by about 20 percent. But electrical stimulation restored their accuracy to normal levels.
Dementia involves far more complicated circuitry than these two layers of the brain. But once scientists better understand exactly how dementia works, it may be possible to combine several implants to each target a specific region.
BLINDNESS
Gene therapy converts cells into photoreceptors, restoring eyesight
Millions of people lose their eyesight when disease damages the photoreceptor cells in their retinas. These cells, called rods and cones, play a pivotal role in vision: They convert incoming light into electrical impulses that the brain interprets as an image.
In recent years, a handful of companies have developed electrode-array implants that bypass the damaged cells. A microprocessor translates information from a video camera into electric pulses that stimulate the retina; as a result, blind subjects in clinical trials have been able to distinguish objects and even read very large type. But the implanted arrays have one big drawback: They stimulate only a small number of retinal cells—about 60 out of 100,000—which ultimately limits a person’s visual resolution.
A gene therapy being developed by Michigan-based RetroSense could replace thousands of damaged retinal cells. The company’s technology targets the layer of the retina containing ganglion cells. Normally, ganglion cells transmit the electric signal from the rods and cones to the brain. But RetroSense inserts a gene that makes the ganglion cells sensitive to light; they take over the job of the photoreceptors. So far, scientists have successfully tested the technology on rodents and monkeys. In rat studies, the gene therapy allowed the animals to see well enough to detect the edge of a platform as they neared it.
The company plans to launch the first clinical trial of the technology next year, with nine subjects blinded by a disease called retinitis pigmentosa. Unlike the surgeries to implant electrode arrays, the procedure to inject gene therapy will take just minutes and requires only local anesthesia. “The visual signal that comes from the ganglion cells may not be encoded in exactly the fashion that they’re used to,” says Peter Francis, chief medical officer of RetroSense. “But what is likely to happen is that their brain is going to adapt.”
PARALYSIS
A brain-machine interface controls limbs while sensing what they touch
Last year, clinical trials involving brain implants gave great hope to people with severe spinal cord injuries. Two paralyzed subjects imagined picking up a cup of coffee. Electrode arrays decoded those neural instructions in real time and sent them to a robotic arm, which brought the coffee to their lips.
But to move limbs with any real precision, the brain also requires tactile feedback. Miguel Nicolelis, a biomedical engineer at Duke University, has now demonstrated that brain-machine interfaces can simultaneously control motion and relay a sense of touch—at least in virtual reality.
For the experiment, Nicolelis’s team inserted electrodes in two brain areas in monkeys: the motor cortex, which controls movement, and the nearby somatosensory cortex, which interprets touch signals from the outside world. Then the monkeys played a computer game in which they controlled a virtual arm—first by using a joystick and eventually by simply imagining the movement. The arm could touch three identical-looking gray circles. But each circle had a different virtual “texture” that sent a distinct electrical pattern to the monkeys’ somatosensory cortex. The monkeys learned to select the texture that produced a treat, proving that the implant was both sending and receiving neural messages.
This year, a study in Brazil will test the ability of 10 to 20 patients with spinal cord injuries to control an exoskeleton using the implant. Nicolelis, an ardent fan of Brazilian soccer, has set a strict timetable for his team: A nonprofit consortium he created, the Walk Again Project, plans to outfit a paraplegic man with a robotic exoskeleton and take him to the 2014 World Cup in São Paulo, where he will deliver the opening kick.
DEAFNESS
Stem cells repair a damaged auditory nerve, improving hearing
Over the past 25 years, more than 30,000 people with hearing loss have received an electronic implant that replaces the cochlea, the snail-shaped organ in the inner ear whose cells transform sound waves into electrical signals. The device acts as a microphone, picking up sounds from the environment and transmitting them to the auditory nerve, which carries them on to the brain.
But a cochlear implant won’t help the 10 percent of people whose profound hearing loss is caused by damage to the auditory nerve. Fortunately for this group, a team of British scientists has found a way to restore that nerve using stem cells.
The researchers exposed human embryonic stem cells to growth factors, substances that cause them to differentiate into the precursors of auditory neurons. Then they injected some 50,000 of these cells into the cochleas of gerbils whose auditory nerves had been damaged. (Gerbils are often used as models of deafness because their range of hearing is similar to that of people.) Three months after the transplant, about one third of the original number of auditory neurons had been restored; some appeared to form projections that connected to the brain stem. The animals’ hearing improved, on average, by 46 percent.
It will be years before the technique is tested in humans. Once it is, researchers say, it has the potential to help not only those with nerve damage but also people with more widespread impairment whose auditory nerve must be repaired in order to receive a cochlear implant.
Cats and humans suffer from similar forms of epilepsy
Epilepsy arises when the brain is temporarily swamped by uncoordinated signals from nerve cells. Research at the Vetmeduni Vienna has now uncovered a cause of a particular type of epilepsy in cats. Surprisingly, an incorrectly channelled immune response seems to be responsible for the condition, which closely resembles a form of epilepsy in humans. The work is published in the current issue of the Journal of Veterinary Internal Medicine.
There is something sinister about epilepsy: the disease affects the very core of our being, our brain. Epileptic attacks can lead to seizures throughout the body or in parts of it. Clouding of consciousness or memory lapses are also possible. The causes are still only partially understood but in some cases brain tumours, infections, inflammations of the brain or metabolic diseases have been implicated.
Epilepsy is not confined to humans and many animals also suffer from it. Together with partners in Oxford and Budapest, Akos Pakozdy and his colleagues at the University of Veterinary Medicine, Vienna have managed to identify the cause of a certain form of epilepsy in cats, in which the body’s own immune system attacks particular proteins in the cell membranes of nerve cells. The symptoms include twitching facial muscles, a fixed stare, chewing motions and heavy dribbling. Based on their clinical experience, the researchers believe that this form of epilepsy is fairly widespread in cats. Interestingly, a highly similar type of epilepsy occurs in humans: an inflammation in the brain, known as limbic encephalitis, leads to epileptic seizures that generally manifest themselves in the arm and the facial muscles on only one side of the body.
Pakozdy and his colleagues have found antibodies in the blood of epileptic cats that react to proteins in the cell membranes of nerve cells. The proteins form the building blocks of ion channels that are involved in the production of nerve signals. The same ion channels are affected in the corresponding human form of epilepsy. They control the membrane’s permeability to potassium ions based on the electric potential across the membrane, thereby helping generate the rapid nerve signals of the so-called action potential.
Immunotherapy for cats?
If the immune system attacks components of these ion channels, the production of nerve signals is disrupted. There is an increased release of neurotransmitters, which leads directly to the symptoms of epilepsy. Previous work – in another group – on human patients has shown that normal anti-epilepsy medication has hardly any effect on this form of epilepsy. However, immunotherapy has proven to be relatively effective. Pakozdy’s work now shows that “limbic encephalitis in cats has the same cause as it does in humans, where the origins have been known for years. It is important that cats with epilepsy are diagnosed early, so that the correct form of therapy can be started. We believe this will dramatically increase the chances of a successful treatment. It seems as though epileptic cats might benefit from treatment with immune preparations.”
(Image: Thinkstock)
Promising new finding for therapies to treat persistent seizures in epileptic patients
In a promising finding for epileptic patients suffering from persistent seizures known as status epilepticus, researchers reported today that new medication could help halt these devastating seizures. To do so, it would have to work directly to antagonize NMDA receptors, the predominant molecular device for controlling synaptic activity and memory function in the brain.
“Despite the development of new medications to prevent seizures, status epilepticus remains a life-threatening condition that can cause extensive brain damage in the patients that survive these persistent seizures,” said David E. Naylor, MD, PhD, a lead researcher at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) and corresponding author of the new study. “Our research holds promise for the development of new therapies to treat this devastating condition because we have found a potential new target for medical intervention that should bolster the current standard therapies to treat the acute seizures. It may also prevent the long-term adverse effects of persistent seizure activity on the brain.”
The research, reported online in the Neurology of Disease journal, used animal models to assess cellular activity in the brain during persistent seizures. It found that the seizure activity seemed to force the NMDA receptors from the interior to the surface of nerve cells causing their activity to increase by approximately 38%.
“The increased presence of the NMDA receptors on the cell surface during these seizures may explain the successful use of NMDA antagonists – medication that inhibits the activity of the NMDA receptors in the brain – in the latter stages of a seizure, long after other medications have stopped working,” said Dr. Naylor. “We concluded that medications that suppress the activity of the NMDA receptors, in conjunction with other medications, may be successful in stopping persistent seizures. Further research is, of course, needed.”
Simple Innovation to Electrodes Makes a Big Difference
The electroencephalogram (EEG) for human uses has been around since 1924. Small metal discs placed along the scalp measure electrical activity in the human brain, important in diagnosing or evaluating epilepsy, sleep disorders and other conditions.
But these electrodes have changed little since their introduction, and are far from perfect. Among other things, they pick up extraneous noise and movement in addition to brain wave activity, often making the readings difficult to interpret.
Walt Besio thinks he has a better way.
The National Science Foundation-funded scientist, who is associate professor of biomedical engineering at the University of Rhode Island, has invented a new and improved electrode, one that produces a performance difference that he says is akin to “taking the rabbit ears you used to have for your television set, and converting to high definition.”
His innovation is relatively simple, but apparently makes a big difference. Besio added two new metal rings around the basic disc, a change that eliminates outside noises and improves spatial resolution.
“EEG has two main problems: It’s very noisy and contaminated with artifacts, and it’s spatial resolution is bad,” he explains. “We have improved the signal-to-noise ratio. It’s four times better than it was before. Because it is now a very local signal, it means we can put electrodes closer together, which improves spatial resolution, meaning you can better determine where the signal is coming from.”
The additional rings work almost like an inner tube tossed on top of a rippling body of water. “The water is flat in the center of the inner tube and choppy on the outside,” he says. “The outer rings on the electrodes behave like that inner tube.”
For researchers and clinicians, having improved electrodes could open up potential new uses, as well as improve current ones-more accurate epilepsy diagnosis, for example, as well as the promise of “reading” someone’s thoughts in the future, with the goal, for example, of activating an otherwise inert body part, such as an arm or leg, and ultimately helping people with spinal cord injuries.
The aim is to have the highly sensitive electrodes first translate a person’s thoughts into electrical impulses that can be read by a computer, then, eventually move to robots, and later, limbs. Other scientists are conducting similar research, but Besio wants to show “that it works better with these types of electrodes.”
