Temple scientists find cancer-causing virus in the brain, potential connection to epilepsy

Researchers at Shriner’s Hospital Pediatric Research Center at the Temple University School of Medicine, and the University of Pennsylvania have evidence linking the human papillomavirus 16 (HPV16) – the most common cause of cervical cancer – to a common form of childhood epilepsy. They have shown for the first time that HPV16 may be present in the human brain, and found that when they added a viral protein to the brains of fetal mice, the mice all demonstrated the same developmental problems in the cerebral cortex associated with this type of epilepsy, called focal cortical dysplasia type IIB (FCDIIB). The findings suggest that the virus could play a role in the development of epilepsy.

The results also mean that doctors may have to re-think their approach to treating this type of epilepsy, and perhaps consider other therapeutic options related to HPV, an infectious disease.

"This is a novel mechanism, and it fills a gap in our understanding about the development of congenital brain malformations," said Peter Crino, MD, PhD, Professor of Neurology at Temple University School of Medicine, and a member of Shriner’s Hospital Pediatric Research Center, and the senior author of a recent report in the Annals of Neurology.

"If our data are correct, future treatment of cortical dysplasia could include targeted therapy against HPV16 infection, with the goal of halting seizures. Identifying an infectious agent as part of the pathogenesis of brain malformations could open up an array of new therapeutic approaches against various forms of epilepsy."

(Image: ASME.org)

Less tau reduces seizures and sudden death in severe epilepsy

Deleting or reducing expression of a gene that carries the code for tau, a protein associated with Alzheimer’s disease, can prevent seizures in a severe type of epilepsy linked to sudden death, said researchers at Baylor College of Medicine and the Mayo Clinic in Jacksonville, Fla., in a report in the current issue of the Journal of Neuroscience.

A growing understanding of the link between epilepsy and some forms of inherited Alzheimer’s disease led to the finding that could point the way toward new drugs for seizure disorders said Dr. Jeffrey Noebels, professor of neurology at BCM, and director of the Blue Bird Circle Developmental Neurogenetics Laboratory.

In her research, Jerrah Holth, a graduate student in molecular and human genetics at BCM who was working with mice with the severe form of epilepsy in Noebel’s laboratory, deleted the gene for tau. She found that reducing or eliminating tau also prevented the seizures in a severe form of epilepsy that has been associated with sudden death and reduced deaths in the animals.

In an earlier experiment, Noebels, in collaboration with Dr. Lennart Mucke at the Gladstone Research Laboratory at the University of California San Francisco, found that mice who carried a human gene that leads to accumulation of the beta amyloid protein and the amyloid plaques that accumulate in the brains of people with Alzheimer’s disease, also had epileptic seizures arising in the hippocampus, the region of the brain associated with memory storage and retrieval.

"This led to the paradigm-shifting hypothesis that excessive neuronal network activity, rather than too little, may contribute to lower cognitive performance and dementia in some forms of Alzheimer’s disease. When this happens, the progression of memory loss may accelerate," said Noebels.

The finding also demonstrated the two disorders may share defects in signaling within brain memory circuits.

The two labs went on to show that deleting the second gene for tau ameliorated both cognitive losses and seizures in the mice whose inherited disorder mimicked Alzheimer’s disease found in humans.

Holth’s finding demonstrates that tau is involved in a far broader range of epilepsy than previously suspected, said Noebels. The type of epilepsy she studied resulted from an inherited potassium ion channel defect that affects the flow of the potassium in and out of nerve cells. She found that removing the gene encoding Tau not only dramatically reduced seizures, but prevented the mice from dying early, which typically happens in these animals.

"Even a partial reduction of the amount of tau protein by 50 percent was highly effective," said Holth. Her finding suggests developing new drugs that lower the normal interactions of the tau protein may reduce seizures and sudden unexpected death for persons with intractable epilepsies, a problem in nearly one-third of the 5 million Americans with this disorder.

Currently, Noebels and his colleagues in the Blue Bird Laboratory are studying whether the loss of tau can correct a seizure disorder once it is already established. If these studies prove fruitful, “the pharmacological discovery programs under development for treatment of Alzheimer’s disease may one day find their way to the epilepsy clinic,” said Noebels.

(Image: ALAMY)

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."

What is déjà vu and why does it happen?

Have you ever experienced a sudden feeling of familiarity while in a completely new place? Or the feeling you’ve had the exact same conversation with someone before?

This feeling of familiarity is, of course, known as déjà vu (a French term meaning “already seen”) and it’s reported to occur on an occasional basis in 60-80% of people. It’s an experience that’s almost always fleeting and it occurs at random.

So what is responsible for these feelings of familiarity?

Despite coverage in popular culture, experiences of déjà vu are poorly understood in scientific terms. Déjà vu occurs briefly, without warning and has no physical manifestations other than the announcement: “I just had déjà vu!”

Many researchers propose that the phenomenon is a memory-based experience and assume the memory centres of the brain are responsible for it.

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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.”

Mild brain cooling after head injury prevents epileptic seizures in lab study

Mild cooling of the brain after a head injury prevents the later development of epileptic seizures, according to an animal study reported this month in the Annals of Neurology.

Epilepsy can result from genetics or brain damage. Traumatic head injury is the leading cause of acquired epilepsy in young adults. It is often difficult to manage with antiepileptic drugs. The mechanisms  behind the onset of epileptic seizures after brain injury are not known . There is currently no treatment to cure it, prevent it, or even limit its severity.

The multi-institutional research team used a rodent model of acquired epilepsy in which animals develop chronic spontaneous recurrent seizures -the hallmark of epilepsy- after a contusive head injury similar to that causing epilepsy in humans. The rats were randomized to either mock-cooling or cooling of the contused brain by no more than 2 Celsius degrees. This degree of cooling, the authors explained, is known to be safe and to decrease mortality of patients with head injury.  The rats  were then monitored for four months after injury and epilepsy was evaluated by intracranial EEG. The contused brain was cooled continuously with special headsets engineered to passively dissipate heat. No Peltier cells or other power sources for refrigeration were needed.

The investigators report that cooling by just 2 degrees celsius for 5 weeks beginning 3 days after injury virtually abolished the later development of epileptic seizure activity. This effect persisted through the end of the study. The treatment induced no additional pathology or inflammation, and restored neuronal activity depressed by the injury.

“These findings demonstrate for the first time that prevention of epileptic seizures after traumatic brain brain injury is possible, and that epilepsy prophylaxis in patients could be achieved more easily than previously thought, said  the lead author of the study,  Raimondo D’Ambrosio, UW associate professor of neurological surgery.  He added that a clinical trial is required to verify the findings in head injury patients.

Brake on nerve cell activity after seizures discovered

Given that epilepsy impacts more than 2 million Americans, there is a pressing need for new therapies to prevent this disabling neurological disorder. New findings from the neuroscience laboratory of Mark S. Shapiro, Ph.D., at The University of Texas Health Science Center at San Antonio, published Dec. 20 in the high-impact scientific journal, Neuron, may provide hope.

“A large fraction of epilepsy sufferers cannot take drugs for their disorder or the existing drugs do not manage it,” said Dr. Shapiro, professor of physiology in the School of Medicine. “As a result, many opt for surgery to remove the hippocampus, a part of the brain where memories are stored but also where seizures are often localized. The heart-wrenching choice is between their memories and the epilepsy.”

Genes go into action
A major finding of the study is that selected genes get switched on during and after a seizure, sending swarms of signals to reduce uncontrolled firing of nerve cells. A medication that amplifies this response after a person’s initial seizure could thus prevent recurrent seizures and the onset of devastating epilepsy.

Uncontrolled electrical activity by specialized electricity-producing proteins in the brain called “ion channels” triggers epileptic seizures. One in 10 people have a lifetime risk of suffering a seizure, which can occur for a variety of reasons including traumatic brain injury, stroke or drug overdoses.

A powerful brake
Although not all seizures lead to epilepsy, some trigger changes in the brain that heighten the risk of the disorder. Dr. Shapiro’s research sheds light on why most isolated seizures do not lead to full-blown epilepsy, whereas others do. An ion channel called the “M-channel” acts as a powerful “brake” on hyper-excitability in the brain. Another organizational protein, called AKAP79, acting much like an air-traffic controller, calls in more M channels as part of neuroprotective response machinery.

Pharmacological therapy to enhance M-channel gene expression or AKAP79 function “could jump-start this neuroprotective mechanism to prevent a seizure from turning into epilepsy,” Dr. Shapiro said. “Administering it right after a traumatic brain injury could be very effective.”

It was not known that electrical activity could regulate M-channel genes, Dr. Shapiro said. Nor was it known that the AKAP79 organizer protein, which coordinates many aspects of M-channel function, could turn on their genes in a person’s DNA. By increasing M-channel expression in the brain, uncontrolled electrical firing of nerve cells in the brain is sharply controlled.

Mouse experiments
The Shapiro lab team records electrical currents and performs imaging in living nerve cells to measure M-channel activity. This study included inducing seizures in healthy mice. After a seizure, gene expression of M-channels in the hippocampus increased more than 10-fold within 24 hours, Dr. Shapiro said. This protective effect was completely absent in mice lacking the mouse version of the AKAP79 gene.

“Because excessive firing of nerve cells is also involved in chronic pains, such as migraines, mood disorders and hypertension, increasing M-channel signals to reduce nerve-cell firing could also likely be effective in treating those conditions,” Dr. Shapiro said.

Study supports link between stress, epileptic seizures

Scientists have long thought that stress plays a role in epileptic seizures, and new evidence suggests that epilepsy patients who believe this is the case experience a different brain response when faced with a nerve-wracking situation.

Researchers from the University of Cincinnati performed functional MRI brain scans during a stressful math exercise on 16 epilepsy patients who pegged stress as a factor in their seizure control and seven patients who did not. While both groups performed similarly on the test, those who perceived stress to have an impact on their epilepsy showed greater brain activation than the others during intimidating parts of the test.

"One of the things we often hear is that a lot of epilepsy patients feel their seizures are affected by stress … but no one had really looked at their [brain response] or other elements of their physiological response," said study author Jane Allendorfer, an instructor of neurology at the University of Alabama at Birmingham. Allendorfer worked at University of Cincinnati while the study was conducted.

"We were a bit surprised to see this difference," she added, "but really excited to see it as well because this is something that hadn’t been done before."

The research was scheduled to be presented Monday at the annual meeting of the American Epilepsy Society, in San Diego. Data presented at scientific conferences often has not been peer-reviewed or published and is considered preliminary.

A brain disorder producing repeated seizures, epilepsy affects more than 2 million people in the United States, according to the U.S. Centers for Disease Control and Prevention. An estimated 50 million to 65 million people are affected by the condition worldwide.

Brain Cooling to Treat Epilepsy Moves Closer to Human Application

Neuroscientists from Japan’s Yamaguchi University today reported during the 66th annual scientific meeting of the American Epilepsy Society (AES) that chronic focal brain cooling suppresses seizures during wakefulness and achieves the effect without significantly affecting brain function. Their research, and that of others in the field, provides critical evidence that this approach to seizure control has reached a stage where testing in humans will soon be possible.

Focal brain cooling is well established as an effective method for suppressing seizures. But the technology for creating a practical device with potential clinical application has only recently become available and tested in rodents. More evidence from large animals and humans is needed prior to testing in clinical trials for drug-resistant epilepsy.

The Yamaguchi researchers implanted two feline and two non-human primates with a titanium cooling plate, or heat exchanger. The brain cooling device was placed in contact with the brain surface over cortex areas responsible for movement and sensation. Seizures were then induced in the motor cortex. Brain wave recordings to assess seizure activity and temperature recordings were performed under wakefulness.

According to Masami Fujii, M.D.,Ph.D., and Takao Inoue, Ph.D., and Michiyasu Suzuki, M.D., Ph.D., who presented the report, seizure discharges were significantly suppressed at 15˚C (59˚F).

“The results of our study suggest that focal brain cooling has a strong effect to suppress the epileptiform seizures under the awake condition,” Dr. Fujii said. “Moreover, implantation of the device for at least five months did not result in detrimental changes in brain tissue subjected to cooling compared to tissue from a similar site in the opposing hemisphere.”