Category: Epilepsy

NewsPsychology (Jan. 26, 2012) — Researchers from the University of Medicine and Dentistry of New Jersey (UMDNJ) and Columbia University have discovered that the most common receptor for the major neurotransmitter in the brain is also present in the lens of the eye, a finding that may help explain links between cataracts, epilepsy and use of a number of widely prescribed antiepileptic and antidepressant drugs. The research appears online in Biochemical and Biophysical Research Communications.

“Recent studies identified associations between increased cataracts and epilepsy, and showed increased cataract prevalence with use of antiepileptic drugs as well as some common antidepressants,” explained corresponding author Peter Frederikse, PhD, of the UMDNJ-New Jersey Medical School. “One common theme linking these observations is that our research showed the most prevalent receptor for the major neurotransmitter in the brain is also present in the lens.”

The research team, which included Norman Kleiman, PhD, of the Mailman School of Public Health at Columbia University, with Mohammed Farooq of the New Jersey Medical School and Rajesh Kaswala, DDS, and Chinnaswamy Kasinathan, PhD, from the New Jersey Dental School, found these glutamate receptor proteins, and specifically a pivotal GluA2 subunit, are expressed in the lens and appear to be regulated in a surprisingly similar manner to the way they are in the brain. In the nervous system, glutamate and GluA receptor proteins underlie memory formation and mood regulation along with being an important factor in epilepsy, considered a primary disorder of the brain. Consistent with this, these receptor proteins are also targets for a number of antiepileptic drugs and antidepressant medications.

“The presence of these glutamate receptors in the lens suggests they contribute to links between brain disease and cataract, as well as providing unintended secondary ‘targets’ of current drugs,” Frederikse said. “Our goal now is to use this information to parse out the potential effects of antiepileptics and antidepressants on these ‘off-target’ sites in the lens, and to determine the role glutamate receptors have in lens biology and pathology.”

This research was supported by a grant from the National Eye Institute of the National Institutes of Health.

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Story Source:

The above story is reprinted from materials provided by University of Medicine and Dentistry of New Jersey (UMDNJ), via Newswise.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Mohammed Farooq, Rajesh H. Kaswala, Norman J. Kleiman, Chinnaswamy Kasinathan, Peter H. Frederikse. GluA2 AMPA glutamate receptor subunit exhibits codon 607 Q/R RNA editing in the lens. Biochemical and Biophysical Research Communications, 2012; DOI: 10.1016/j.bbrc.2012.01.009

Neuroscientists may one day be able to hear the imagined speech of a patient unable to speak due to stroke or paralysis, according to University of California, Berkeley, researchers.

These scientists have succeeded in decoding electrical activity in the brain's temporal lobe — the seat of the auditory system — as a person listens to normal conversation. Based on this correlation between sound and brain activity, they then were able to predict the words the person had heard solely from the temporal lobe activity.

"This research is based on sounds a person actually hears, but to use it for reconstructing imagined conversations, these principles would have to apply to someone's internal verbalizations," cautioned first author Brian N. Pasley, a post-doctoral researcher in the center. "There is some evidence that hearing the sound and imagining the sound activate similar areas of the brain. If you can understand the relationship well enough between the brain recordings and sound, you could either synthesize the actual sound a person is thinking, or just write out the words with a type of interface device."

"This is huge for patients who have damage to their speech mechanisms because of a stroke or Lou Gehrig's disease and can't speak," said co-author Robert Knight, a UC Berkeley professor of psychology and neuroscience. "If you could eventually reconstruct imagined conversations from brain activity, thousands of people could benefit."

In addition to the potential for expanding the communication ability of the severely disabled, he noted, the research also "is telling us a lot about how the brain in normal people represents and processes speech sounds."

Pasley and his colleagues at UC Berkeley, UC San Francisco, University of Maryland and The Johns Hopkins University report their findings Jan. 31 in the open-access journal PLoS Biology.

Help from epilepsy patients

They enlisted the help of people undergoing brain surgery to determine the location of intractable seizures so that the area can be removed in a second surgery. Neurosurgeons typically cut a hole in the skull and safely place electrodes on the brain surface or cortex — in this case, up to 256 electrodes covering the temporal lobe — to record activity over a period of a week to pinpoint the seizures. For this study, 15 neurosurgical patients volunteered to participate.

Pasley visited each person in the hospital to record the brain activity detected by the electrodes as they heard 5-10 minutes of conversation. Pasley used this data to reconstruct and play back the sounds the patients heard. He was able to do this because there is evidence that the brain breaks down sound into its component acoustic frequencies — for example, between a low of about 1 Hertz (cycles per second) to a high of about 8,000 Hertz -that are important for speech sounds.

Pasley tested two different computational models to match spoken sounds to the pattern of activity in the electrodes. The patients then heard a single word, and Pasley used the models to predict the word based on electrode recordings.

"We are looking at which cortical sites are increasing activity at particular acoustic frequencies, and from that, we map back to the sound," Pasley said. He compared the technique to a pianist who knows the sounds of the keys so well that she can look at the keys another pianist is playing in a sound-proof room and "hear" the music, much as Ludwig van Beethoven was able to "hear" his compositions despite being deaf.

The better of the two methods was able to reproduce a sound close enough to the original word for Pasley and his fellow researchers to correctly guess the word.

"We think we would be more accurate with an hour of listening and recording and then repeating the word many times," Pasley said. But because any realistic device would need to accurately identify words heard the first time, he decided to test the models using only a single trial.

"This research is a major step toward understanding what features of speech are represented in the human brain" Knight said. "Brian's analysis can reproduce the sound the patient heard, and you can actually recognize the word, although not at a perfect level."

Knight predicts that this success can be extended to imagined, internal verbalizations, because scientific studies have shown that when people are asked to imagine speaking a word, similar brain regions are activated as when the person actually utters the word.

"With neuroprosthetics, people have shown that it's possible to control movement with brain activity," Knight said. "But that work, while not easy, is relatively simple compared to reconstructing language. This experiment takes that earlier work to a whole new level."

Based on earlier work with ferrets

The current research builds on work by other researchers about how animals encode sounds in the brain's auditory cortex. In fact, some researchers, including the study's coauthors at the University of Maryland, have been able to guess the words ferrets were read by scientists based on recordings from the brain, even though the ferrets were unable to understand the words.

The ultimate goal of the UC Berkeley study was to explore how the human brain encodes speech and determine which aspects of speech are most important for understanding.

"At some point, the brain has to extract away all that auditory information and just map it onto a word, since we can understand speech and words regardless of how they sound," Pasley said. "The big question is, What is the most meaningful unit of speech? A syllable, a phone, a phoneme? We can test these hypotheses using the data we get from these recordings."

Coauthors of the study are electrical engineers Stephen V. David, Nima Mesgarani and Shihab A. Shamma of the University of Maryland; Adeen Flinker of UC Berkeley's Helen Wills Neuroscience Institute; and neurologist Nathan E. Crone of The Johns Hopkins University in Baltimore, Md. The work was done principally in the labs of Robert Knight at UC Berkeley and Edward Chang, a neurosurgeon at UCSF.

Chang and Knight are members of the Center for Neural Engineering and Prostheses, a joint UC Berkeley/UCSF group focused on using brain activity to develop neural prostheses for motor and speech disorders in disabling neurological disorders.

The work is supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and the Humboldt Foundation.

Scientists at Emory University School of Medicine have identified a new group of compounds that may protect brain cells from inflammation linked to seizures and neurodegenerative diseases.

The compounds block signals from EP2, one of the four receptors for prostaglandin E2, which is a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Chemicals that could selectively block EP2 were not previously available. In animals, the EP2 blockers could markedly reduce the injury to the brain induced after a prolonged seizure, the researchers showed.

The results were published online this week in the Proceedings of the National Academy of Sciences Early Edition.

"EP2 is involved in many disease processes where inflammation is showing up in the nervous system, such as epilepsy, stroke and neurodegenerative diseases," says senior author Ray Dingledine, PhD, chairman of Emory's Department of Pharmacology. "Anywhere that inflammation is playing a role via EP2, this class of compounds could be useful. Outside the brain, EP2 blockers could find uses in other diseases with a prominent inflammatory component such as cancer and inflammatory bowel disease."

Prostaglandins are the targets for non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. NSAIDSs inhibit enzymes known as cyclooxygenases, the starting point for generating prostaglandins in the body. Previous research indicates that drugs that inhibit cyclooxygenases can have harmful side effects. For example, sustained use of aspirin can weaken the stomach lining, coming from prostaglandins' role in the stomach. Even drugs designed to inhibit only cyclooxygenases involved in pain and inflammation, such as Vioxx, have displayed cardiovascular side effects.

Dingledine's team's strategy was to bypass cyclooxygenase enzymes and go downstream, focusing on one set of molecules that relay signals from prostaglandins. Working with Yuhong Du in the Emory Chemical Biology Discovery Center, postdoctoral fellows Jianxiong Jiang, Thota Ganesh and colleagues sorted through a library of 262,000 compounds to find those that could block signals from the EP2 prostaglandin receptor but not related receptors. One of the compounds could prevent damage to neurons in mice after "status epilepticus," a prolonged drug-induced seizure used to model the neurodegeneration linked to epilepsy. The team found that a family of related compounds had similar protective effects.

Dingledine says that the compounds could become valuable tools for exploring new ways to treat neurological diseases. However, given the many physiological processes prostaglandins regulate, more tests are needed, he says. Prostaglandin E2 is itself a drug used to induce labor in pregnant women, and female mice engineered to lack the EP2 receptor are infertile, so the compounds would need to be tested for effects on reproductive organs, for example.

The research was supported by the National Institutes of Health.

A neuropeptide called Substance P is the cause of seizures in patients with brains infected by the pork tapeworm (Taenia solium), said Baylor College of Medicine researchers in a report that appears online in the open access journal PLoS Pathogens.

"Neurocysticercosis or the tapeworm parasitic infection in the brain, is the major cause of acquired seizures," said Dr. Prema Robinson, assistant professor of medicine — infectious diseases, and corresponding author of the report. "It is particularly important to understand the source of these seizures in order to develop ways to treat and prevent them."

Substance P is a neuropeptide (a small protein-like molecule involved in neuron-to-neuron communication.) It is produced by neurons, endothelial cells (the cells that line blood vessels) and cells involved in host defense. Discovered in the 1930s, it has long been recognized as a pain transmitter. However, in recent years, it has also been found to play a role in many other functions.

Inflammation of the brain

Robinson realized that Substance P is involved in inflammation and wondered if it might be involved in seizure activity.

Robinson and her colleagues — including one from Tufts Medical Center in Boston — found Substance P in autopsies of the brains of patients who had the tapeworm infection. They did not find Substance P in uninfected brains.

"As long as the parasite is alive, nothing happens," said Robinson. However, once the worm dies, the body responds with chemicals that recruit immune system cells to the site of infection, causing inflammation. Her studies showed that the cells that produce Substance P are found mainly in areas of inflammation near the dead worms.

Animals injected with Substance P alone or with extracts from the areas of inflammation (granulomas) near the worms in infected mice suffered severe seizures, she said.

When the rodents received the drug that blocks the Substance P receptor, they did not have seizures, she said.

In addition, mice that lacked the Substance P receptor did not have seizures even when injected with the extracts of granulomas from infected mice. In addition, granuloma extracts from mice that lacked the cells that make Substance P did not induce seizures.

Medications block receptor

These findings have implications for people, who often suffer seizures during treatment for the tapeworm infection, she said. As the worms die, inflammatory cells rush to the scene and the seizures begin. There are medications known to block the receptor for Substance P. These medications may prove to be the most effective means of treating and preventing seizures in these patients.

Robinson plans to look at the role Substance P may play in other diseases associated with seizures such as cancer and tuberculosis.

Others who took part in her research include Armandina Garza, Jose A. Serpa, Jerry Clay Goodman, Kristian T. Eckols, Bahrom Firozgary, and David J. Tweardy, all of BCM and Joel Weinstock of Tufts Medical Center.

Funding for this work came from a grant from the National Institutes of Health.

A team led by a University of British Columbia professor has developed a new class of drugs that completely suppress absence seizures — a brief, sudden loss of consciousness — in rats, and which are now being tested in humans.

Absence seizures, also known as "petit mal seizures," are a symptom of epilepsy, most commonly experienced by children. During such episodes, the person looks awake but dazed. The seizures, arising from a flurry of high-frequency signals put out by the neurons of the thalamus, can be dangerous if they occur while a person is swimming or driving, and can also interrupt learning.

Available medications don't completely control such seizures in many patients. They also cause severe side effects, including sleepiness, blurred vision and diminished motor control.

A Canadian-Australian team, led by neuroscientist Terrance P. Snutch, a Canada Research Chair in the Michael Smith Laboratories at UBC, developed new drugs with a different target — the flow of calcium into brain cells. Their findings were recently published in Science Translational Medicine.

The new drugs, known as Z941 and Z944, block the flow of calcium ions into those neurons. When given to rats with absence epilepsy, they suppressed seizures by 85 to 90 per cent.

The team, which included collaborators at Zalicus Pharmaceuticals Ltd. of Vancouver and the University of Melbourne, was surprised to find that when seizures did occur, they were also of shorter duration; existing medications don't have any effect on the length of seizures.

The first phase of human clinical trials of Z944 began in December, with results expected later this year.

"Z941 and Z944 were designed to target a specific type of nerve cell calcium channel associated with epilepsy, as well as other hyper-excitability disorders such as chronic pain," says Snutch, a professor in the departments of psychiatry and zoology. "The dramatic effect of the drugs in rats with absence epilepsy, together with the drugs' ability to be administered orally and easily absorbed, and its good safety profile in animals, provide us with cautious optimism for the current clinical trial."

Dr. Snutch's translational research program has previously resulted in the development of drugs to treat chronic pain, one of which is currently undergoing clinical trials and another that has been approved by the U.S. Food and Drug Administration and is available to patients.

While the thought of any type of surgery can be disconcerting, the thought of brain surgery can be downright frightening. But for people with a particular form of epilepsy, surgical intervention can literally be life-restoring.

Yet among people who suffer from what's known as medically intractable epilepsy, in which seizures are resistant to drugs, only a small fraction will seek surgery, seeing it only as a last resort. As a result, they continue to suffer seizures year after year. They can't drive, they can't work and they lose cognitive function as the years pass. Premature death is not uncommon.

But a multi-center study led by researchers at UCLA shows that for people suffering from intractable temporal lobe epilepsy, the most common form of intractable epilepsy, early surgical intervention followed by antiepileptic drugs stopped their seizures, improved their quality of life and helped them avoid decades of disability.

The report appears in the March 7 edition of the Journal of the American Medical Association.

"In short, they got their lives back," said Dr. Jerome Engel, the study's principal investigator and director of the UCLA Seizure Disorder Center.

But the frustration of Engel and his colleagues is this: Few patients are referred to them for surgical evaluation, and those who are have had epilepsy for an average of 22 years.

"By then, it's often too late," he said. "These people will likely remain disabled for life."

Epilepsy is a brain disorder that produces sudden and repeated seizures that last from a few seconds to several minutes. Seizures are brief attacks of altered consciousness, muscle control or sensory perception. During a seizure, some brain cells behave abnormally, firing repeatedly. This usually begins with a small group of cells and spreads to involve a larger area of the brain.

Epilepsy affects nearly 3 million Americans and 50 million people worldwide; the health burden caused by the disease is equivalent to that of lung cancer in men and breast cancer in women. In the U.S., the 30-40 percent of epilepsy patients who suffer from medically intractable epilepsy account for 80 percent of the cost of the disorder.

For the study, 16 epilepsy centers nationwide recruited 38 individuals suffering from mesial temporal lobe epilepsy that was determined to be intractable — that is, the patients were still having seizures after trying two different anti-epileptic drugs (the international definition of medical intractability). Those recruited had to be within two years of having their disease declared intractable. Of the study participants, 15 underwent surgery and 23 were assigned to a program of best medical care.

The researchers found that after two years, 85 percent of the participants who underwent surgery were seizure-free in the second year after the procedure; by comparison, none in the medical care group were seizure-free.

The surgical group also reported a significantly higher quality of life, a significant increase in independence, and an improved willingness and ability to socialize with friends and family. The number of individuals who reported being able to drive a car rose from 7 percent to 80 percent in the surgical group at the end of two years. Cognitive problems such as memory loss were similar between both groups.

"The results of this study are very encouraging," said Engel, who holds the Jonathan Sinay Chair in Epilepsy at UCLA. "Surgical treatment for temporal lobe epilepsy soon after the failure of two trials of anti-epileptic drugs stops seizures and improves quality of life. Continuing anti-epileptic drug treatment alone does not.

"So the message is clear: Early surgery, before the adverse social and psychological consequences of seizures become irreversible, offers the best opportunity to avoid a lifetime of disability."

"This study shows that early surgical intervention works, it stops seizures and it improves quality of life," said Dr. Karl Kieburtz, director of the Center for Human Experimental Therapeutics at the University of Rochester Medical Center, which served as the coordinating center for the study. "Individuals with epilepsy that is not controlled with medicine should be evaluated for surgical intervention at a comprehensive epilepsy center — not after decades of poor response to medicine but within two years. And if they are a surgical candidate, they should give strong consideration to that approach."

The results were statistically significant, even though the study was terminated early due to slow enrollment. The study originally was intended to follow 200 patients, but only 38 ultimately were recruited. While some patients who were referred did not meet the study's criteria, the major problem was a lack of referrals, researchers said. Engel is not sure why.

"Partly, it has to do with the larger number of available anti-epileptic drugs, so neurologists in the community will try more combinations of medications," he said. "Also, there are many misconceptions about surgical criteria that prevent the referral of good candidates. If patients have intractable seizures, they should be given the opportunity to be evaluated at an epilepsy center. But the biggest reason is fear — that's often cited by patients and their physicians as a reason for continuing drug therapy. They see surgery as a last resort. And this study shows that that's just wrong."

Other authors of the study included John Stern, Itzhak Fried, Sandra Dewar and Harry Vinters, of UCLA; Michael P. McDermott, John Langfitt, Giuseppe Erba and Irenita Gardiner, of the University of Rochester Medical Center; Michael Sperling and Scott Mintzer, of Jefferson University; Samuel Wiebe, of the University of Calgary; and Margaret Jacobs, of the National Institute of Neurological Disorders and Stroke.

The study was funded by the National Institute of Neurological Disorders and Stroke. The authors report no conflict of interest.

A new study finds that low concentrations of the chemical methylisothiazolinone has subtle but measurable negative effects on the neural development of tadpoles. The chemical is found in some cosmetics, although the study does not provide any evidence that cosmetics are unsafe for humans.

Scientists, health officials, and manufacturers already know that a chemical preservative found in some products, including cosmetics, is harmful to people and animals in high concentrations, but a new Brown University study in tadpoles reports that it can also interrupt neurological development even in very low concentrations.

In the cosmetics industry, the biocide methylisothiazolinone or MIT, is considered safe at concentrations of less than 100 parts per million. Lab studies, however, have found that lower concentrations affected the growth of animal neurons. Picking up from there, the Brown researchers performed a series of experiments to investigate how 10 days of exposure at concentrations as low as 1.5 ppm would affect whole, living tadpoles as they develop. Their results appear in advance online in the journal Neuroscience.

"The lower concentrations we studied didn't kill the animals or cause any big deformities or affect the behavior you'd see just by looking at them," said Carlos Aizenman, associate professor of neuroscience and the study's senior author. "But then we decided to do a series of functional tests and we found that exposure to this compound during a period of development that's critical for the fine wiring of the nervous system disrupted this period of fine tuning."

Aizenman emphasized that there is no evidence in the study that any products with MIT, such as shampoos or cosmetics, are harmful to consumers.

Neurotoxic effects

When Aizenman and lead author Ariana Spawn explored the consequences of exposing tadpoles to two nonlethal concentrations, 1.5 ppm and 7.6 ppm, they found some deficits both in behavior and in basic brain development.

In one experiment they shined moving patterns of light into one side of the tadpole tanks from below. As they expected, the unexposed tadpoles avoided the light patterns, swimming to the other side. Tadpoles that had been exposed to either concentration of MIT, however, were significantly less likely to avoid the signals.

In another experiment, Aizenman and Spawn, who was an undergraduate at the time and has since graduated, exposed the tadpoles to another chemical known to induce seizures. The tadpoles who were not exposed to MIT and those exposed to the lower concentration each had the same ability to hold off seizures, but the ones who had been exposed to the 7.6 ppm concentration succumbed to the seizures significantly more readily.

In these experiments, seizure susceptibility had nothing to do with epilepsy, Aizenman said, but was instead a measure of more general neural development.

After observing the two significant behavioral effects in the tadpoles, Aizenman and Spawn then sought the underlying physiological difference between exposed and unexposed tadpoles that might cause them. They performed an electrophysiological analysis of each tadpole's optic tectum, a part of the brain responsible for processing visual information. They found evidence that the chemical seems to have stunted the process by which tadpoles prune and refine neural connections, a key developmental step.

"The neural circuits act like the neural circuits of a much more immature tadpole," Aizenman said. "This is consistent with the previous findings in cell cultures."

Aizenman said consumers should know about the study's results and pay attention to the ingredients in the products they use, but should not become worried based on the basic science study.

Aizenman said one area where further studies may be warranted is in cases of repeated exposure in industrial or occupational settings, but the study's broader message may be that chemical manufacturers and independent labs should test more for neurodevelopmental effects of even low concentrations of products. In the specific case of MIT in tadpoles, he noted, "It's resulting in a non-obvious but real deficit in neural function."

Brown University and the Whitehall Foundation funded the research.

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Journal Reference:

1. Ariana Spawn, Carlos Aizenman. Abnormal visual processing and increased seizure susceptibility result from developmental exposure to the biocide methylisothiazolinone. Neuroscience, 2012; DOI: 10.1016/j.neuroscience.2011.12.052

Researchers at the Stanford University School of Medicine have identified a brain-circuit defect that triggers absence seizures, the most common form of childhood epilepsy.

In a study to be published online Aug. 21 in Nature Neuroscience, the investigators showed for the first time how defective signaling between two key brain areas — the cerebral cortex and the thalamus — can produce, in experimental mice, both the intermittent, brief loss of consciousness and the roughly three-times-per-second brain oscillations that characterize absence seizures in children. Young patients may spontaneously experience these seizures up to hundreds of times per day, under quite ordinary circumstances.

The new findings may lead to a better understanding of how ordinary, waking, sensory experiences can ignite seizures, said John Huguenard, PhD, the study's senior author.

Epilepsy, a pattern of recurrent seizures, will affect about one in 26 people over their lifetime. Absence, or petit-mal, seizures — the form that epilepsy usually takes among children ages 6-15 — feature a sudden loss of consciousness lasting 15 seconds or less. These seizures can be so subtle that they aren't noticed, or are mistaken for lack of attention. The patient remains still for several seconds, as if frozen in place. Usually, a person who experiences an absence seizure has no memory of the episode.

"It's like pushing a pause button," said Huguenard, professor of neurology and neurological sciences and of molecular and cellular physiology.

Inside the brain, however, things more resemble an electrical storm than a freeze-frame.

The brain is, in essence, a complicated electrochemical calculating machine employing circuits that process information and share it with other, often-remote circuits, resulting in networks of sometimes staggering complexity. A nerve cell can be thought of as a long, branching wire that can transmit electrical signals along its length and then relay these signals to up to thousands of other nerve cells by secreting specialized chemicals at points of contact with other "wires." Depending on the nature of the signaling interaction, the result can be either excitatory (increasing the likelihood that the next nerve cell in the relay will fire its own electrical impulse) or inhibitory (decreasing that likelihood).

During an absence seizure, the brain's electrical signals spontaneously coalesce into rhythmic oscillations, beginning in the neighborhood of two important brain areas, the cortex and the thalamus. Exactly where or how this pattern is initiated has been a source of controversy, said the study's lead author, Jeanne Paz, PhD, a postdoctoral researcher in Huguenard's lab.

"In order to develop better therapies, it is important to understand where and how the oscillations originate," Paz said.

The cortex and thalamus share an intimate relationship. The cortex, like a busy executive, assesses sensory information, draws conclusions, makes decisions and directs action.

To keep from being constantly bombarded by distracting sensory information from other parts of the body and from the outside world, the cortex flags its activity level by sending a steady stream of signals down to the thalamus, where nearly all sensory signals related to the outside world are processed for the last time before heading up to the cortex. In turn, the thalamus acts like an executive assistant, sifting through sensory inputs from the eyes, ears and skin, and translating their insistent patter into messages relayed up to the cortex. The thalamus carefully manages those messages in response to signals from the cortex.

These upward- and downward-bound signals are conveyed through two separate nerve tracts that each stimulate activity in the other tract. In a vacuum, this would soon lead to out-of-control mutual excitement, similar to a microphone being placed too close to a P.A. speaker. But there is a third component to the circuit: an inhibitory nerve tract that brain scientists refer to as the nRT. This tract monitors signals from both of the other two, and responds by damping activity. The overall result is a stable, self-modulating system that reliably delivers precise packets of relevant sensory information but neither veers into a chaotic state nor completely shuts itself down.

In bioengineered mice that the Stanford team studied with Wayne Frankel, PhD, of the Jackson Laboratory in Bar Harbor, Maine, this circuit is broken because the GluA4 receptor, a protein component of cells critical to the stimulation of nRT cells, is missing. Notably, these mice are prone to intermittent absence seizures. The researchers aimed to find out why, by separately studying the mouse's key corticothalamic-circuit components. Using a technique called optogenetics, they were able to selectively switch each of the two stimulatory tracts' signal transmissions on or off at will.

The researchers observed that, as expected, signals from one of the two tracts failed to excite the receptor-deficient mice's inhibitory nRT cells. Oddly, though, signals from the other tract continued to get through to the nRT tract just fine — "a paradoxical and totally surprising result," said Huguenard.

This leaves nRT receiving signals from one tract, but not the other, which upsets the equilibrium usually maintained by the circuit. As a result, one of its components — the thalamocortical tract — is thrown into overdrive. Its constituent nerve cells begin firing en masse, rather than faithfully obeying the carefully orchestrated signals from the cortex. This in turn activates the nRT to an extraordinary degree, because its contact with the thalamocortical tract is not affected in these mice.

Huguenard estimates that, typically, only a very small percentage of nRT cells are firing at a given time. In the face of over-amped signaling from the thalamocortical tract, however, the fraction of excited nRT nerve cells rose much higher, perhaps as much as 50 percent — enough to effectively silence all signaling from the thalamus to the cortex — a key first step in a seizure.

But the shutdown was transitory. A property of thalamic cells (like other nerve cells) is that when they've been inhibited they tend to overreact and respond even more strongly than if they had been left alone. After a burst of nRT firing, this tract's overall inhibition of the thalamocortical tract all but halted activity there for about one-third of a second. Like boisterous schoolchildren who can shut up only until the librarian leaves the room, the thalamocortical cells resumed shouting in unison as soon as the inhibition stopped, and a strong volley of signaling activity headed for the cortex. Then the nRT's inhibitory signaling recommenced, and the stream of signals from the thalamus to the cortex ceased once again.

This three-Hertz cycle of oscillations consisting of alternating quiet and exuberant periods repeated over the course of 10 or 15 seconds was the electrophysiology of a seizure.

Whether the specific nRT defect in the bioengineered mice is important in human absence seizures is not yet known, Huguenard cautioned. Most individuals who suffer from these seizures appear to have "normal" nerve cells (individually indistinguishable from those of non-epileptics) and normally formed circuits as well. But now his group has a model experimental system with which they can try to determine why ordinary experiences can trigger these seizures in everyday life. Behavioral experiments are under way in his lab to see what kinds of common sensory exposures can trip off a similar circuit malfunction in normal mice. The resulting observations may someday help patients control their own exposures to minimize seizures, Huguenard said.

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Journal Reference:

1. Jeanne T Paz, Astra S Bryant, Kathy Peng, Lief Fenno, Ofer Yizhar, Wayne N Frankel, Karl Deisseroth, John R Huguenard. A new mode of corticothalamic transmission revealed in the Gria4−/− model of absence epilepsy. Nature Neuroscience, 2011; DOI: 10.1038/nn.2896

Almost everyone has experienced one memory triggering another, but explanations for that phenomenon have proved elusive. Now, University of Pennsylvania researchers have provided the first neurobiological evidence that memories formed in the same context become linked, the foundation of the theory of episodic memory.

The research was conducted by professor Michael Kahana of the Department of Psychology in the School of Arts and Sciences and graduate student Jeremy R. Manning, of the Neuroscience Graduate Group in Penn's Perelman School of Medicine. They collaborated with Gordon Baltuch and Brian Litt of the departments of Neurology and Psychology at the medical school and Sean M. Polyn of Vanderbilt University.

Their research was published in the journal Proceedings of the National Academy of Sciences.

"Theories of episodic memory suggest that when I remember an event, I retrieve its earlier context and make it part of my present context," Kahana said. "When I remember my grandmother, for example, I pull back all sorts of associations of a different time and place in my life; I'm also remembering living in Detroit and her Hungarian cooking. It's like mental time travel. I jump back in time to the past, but I'm still grounded in the present."

To investigate the neurobiological evidence for this theory, the Penn team combined a centuries-old psychological research technique — having subjects memorize and recall a list of unrelated words — with precise brain activity data that can only be acquired via neurosurgery.

The study's participants were all epilepsy patients who had between 50 and 150 electrodes implanted throughout their brains. This was in an effort to pinpoint the region of the brain where their seizures originated. Because doctors had to wait for seizures to naturally occur in order to study them, the patients lived with the implanted electrodes for a period of weeks.

"We can do direct brain recordings in monkeys or rats, but with humans one can only obtain these recordings when neurosurgical patients, who require implanted electrodes for seizure mapping, volunteer to participate in memory experiments," Kahana said. "With these recordings, we can relate what happens in the memory experiment on a millisecond-by-millisecond basis to what's changing in the brain."

The memory experiment consisted of patients memorizing lists of 15 unrelated words. After seeing a list of the words in sequence, the subjects were distracted by doing simple arithmetic problems. They were then asked to recall as many words as they could in any order. Their implanted electrodes measured their brain activity at each step, and each subject read and recalled dozens of lists to ensure reliable data.

"By examining the patterns of brain activity recorded from the implanted electrodes," Manning said, "we can measure when the brain's activity is similar to a previously recorded pattern. When a patient recalls a word, their brain activity is similar to when they studied the same word. In addition, the patterns at recall contained traces of other words that were studied prior to the recalled word."

"What seems to be happening is that when patients recall a word, they bring back not only the thoughts associated with the word itself but also remnants of thoughts associated with other words they studied nearby in time," he said.

The findings provide a brain-based explanation of a memory phenomenon that people experience every day.

"This is why two friends you met at different points in your life can become linked in your memory," Kahana said. "Along your autobiographical timeline, contextual associations will exist at every time scale, from experiences that take place over the course of years to experiences that take place over the course of minutes, like studying words on a list."

The research was supported by the National Institutes of Mental Health and the Dana Foundation.

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Journal Reference:

1. J. R. Manning, S. M. Polyn, G. H. Baltuch, B. Litt, M. J. Kahana. Oscillatory patterns in temporal lobe reveal context reinstatement during memory search. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1015174108

A recent multi-center study determined that women with generalized tonic-clonic seizures (GTCS) had a greater number of seizures during anovulatory cycles — menstrual cycles where an egg is not released — than in cycles where ovulation occurs. According to the study published in Epilepsia, a journal of the International League Against Epilepsy (ILAE), reproductive steroids may play a role in GTCS occurrence.

Medical evidence has shown that sex hormones, estradiol and progesterone, have neuroactive properties that can affect seizures. Previous studies by Andrew Herzog, MD, MSc, of Beth Israel Deaconess Medical Center in Boston, Massachusetts and colleagues found that ratios of hormone levels in the blood differ in relation to the ovulatory status of menstrual cycles, with anovulatory cycles having higher estradiol-progesterone ratios during the second half of the menstrual cycle (luteal phase) compared to ovulatory cycles. Further studies have determined that anovulatory cycles are more common among women with epilepsy than in the general population.

To expand on their prior research, Dr. Herzog and colleagues used data collected during the Progesterone Trial Study — a 3-month investigation of progesterone therapy for focal onset seizures that are difficult to control. Of the 281 women who participated, 92 had both anovulatory and ovulatory cycles during the study period, with progesterone levels of 5 ng/ml measured in the latter part of the menstrual cycle, designating ovulation.

Among the 281 study participants, 37% had GTCS, 81% had complex partial seizures (CPS) and 38% had simple partial seizures (SPS). In the 92 women who had both ovulatory and anovulatory cycles, the seizure percentages were slightly lower, but not significantly different. Researchers determined that the average daily seizure frequency was 30% greater in the women during their anovulatory cycles than in those cycles were ovulation occurred. Seizure frequency did not differ significantly for CPS, SPS, or for all seizures combined.

"Our results showed that GTCS frequency during anovulatory cycles correlate with proportional increases in estradiol-progesterone level ratios, suggesting sex hormones contribute to seizure incidence," concluded Dr. Herzog. "Efficacy results from the phase 3 clinical trial of a progesterone supplement that generated the data for the current study are forthcoming, and may provide a much needed treatment option to control seizures in women with epilepsy."

According to the National Institute of Neurological Disorders and Stroke (NINDS), tonic-clonic seizures, formerly known as grand mal seizures, are the most common type of generalized seizure and cause symptoms that include stiffening of the body, repeated jerking of the arms or legs, and loss of consciousness. The Epilepsy Foundation estimates that 200,000 new cases of epilepsy are diagnosed each year in the U.S., and roughly half of those are generalized onset seizures.

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Journal Reference:

1. Andrew G. Herzog, Kristen M. Fowler, Michael R. Sperling, Joyce D. Liporace, Laura A. Kalayjian, Christianne N. Heck, Gregory L. Krauss, Barbara A. Dworetzky, Page B. Pennell, and the Progesterone Trial Study Group. Variation of Seizure Frequency with Ovulatory Status of Menstrual Cycles. Epilepsia, 2011; DOI: 10.1111/j.1528-1167.2011.03194.x