Stimulating New Therapy for Epilepsy

Electrodes placed on the forehead can ease seizures and more.

Electric pulses delivered to the forehead by external electrodes could cut many epilepsy sufferers' seizure rates in half, according to the results of a recent trial. Unlike other nerve-stimulation approaches that require surgical implants, this temporary device could allow physicians to ascertain whether their patients would benefit from more permanent invasive approaches.

Epilepsy affects about two million people in the U.S., and medications can help keep seizures to a minimum in a majority of patients. However, as many as 30 percent of people with the disorder are drug resistant. Because seizures occur when the brain's electrical impulses go awry, a number of devices that stimulate the brain electrically are currently under testing, based on the theory that external stimulation can disrupt those abnormal impulses and interrupt or even prevent the aberrant signals.

The vagus nerve stimulator (VNS), an implant in the chest that sends electric pulses to an electrode wrapped around a nerve in the left side of the neck, has already been approved by the U.S. Food and Drug Administration. But VNS is expensive (costing $20,000 or more), and it's only effective in about 40 percent of patients—and there's no presurgical way to predict who will benefit. The new, external device uses the same basic principle but exploits the more superficial trigeminal nerve—a large cranial nerve that emerges from deep in the brain and branches to run down both sides of the face.

"The trigeminal nerve projects to key parts of the brain that modulate seizure and mood," says Christopher DeGiorgio, a neurologist at the University of California at Los Angeles and the inventor of the device. "I started to think about using it because it can be stimulated noninvasively."

With the trigeminal neural stimulator (TNS), a long, butterfly-shaped sticker electrode is affixed to the forehead. Small wires, which can be tucked behind the ears, lead from the electrodes to a small pulse generator that can be worn in a back pocket for 12 to 16 hours each day. According to the results of a 50-person, placebo-controlled study that DeGiorgio presented in April, the TNS device showed similar efficacy to the implantable VNS; about 40 percent of those in the test group experienced at least 50 percent fewer seizures.

"The preliminary results and open-label studies appear promising," says Robert Fischer, a neurologist at Stanford University's epilepsy center who was not involved in the research. "We put VNS devices into the chest and neck of people and ultimately find that it's substantially helpful in no more than 50 percent. That means the other 50 percent have had a surgical procedure without benefit. The ability to do a trial run would be helpful."For epilepsy patients experiencing success on TNS, the device has been life-changing. "I was getting 20 seizures a month when I started using it, and now I'm down to eight," says Walter Cortes, 29, of Reseda, California, who participated in the study. When Cortes was hospitalized for a case of pancreatitis caused by one of his epilepsy medications, he suspended his use of the device, and the seizures returned in full force. "That's when I realized that machine was something special."

Beyond suppression of seizures, many in the TNS trial reported an improvement in mood. (Epilepsy patients commonly suffer from depression.) "The trigeminal nerve projects to a brain-stem structure that produces norepinephrine, which regulates mood, attention, and anxiety," DeGiorgio says. When the TNS device was tested in a small trial on treatment-resistant depression, it showed such promising results—with four out of five patients going into remission after eight weeks of nightly TNS treatment—that a larger 20-person study is now under way. "The technology is so elegant and simple that it's almost hard to believe," says Ian Cook, the psychiatrist and neuroscience researcher at UCLA who's heading the depression trials.  

The current trials use an off-the-shelf stimulator, but startup NeuroSigma has licensed the approach. The company is now developing a proprietary device, working with researchers on clinical trials for epilepsy, depression, and PTSD, and developing an implantable version for patients who find relief with the temporary one.

An Ultra-High-Definition 3-D TV

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Brighter 3-D: This 70-inch 3-D television from Samsung forms images with eight billion pixels, a density enabled by use of metal oxide materials in the control electronics.
Credit: Samsung

COMPUTING

An Ultra-High-Definition 3-D TV

New electronics enable a jump in performance in a prototype display made by Samsung.

Samsung has shown off a prototype of an ultra-high-definition 3-D television. The 70-inch prototype uses a novel electronic circuitry to control eight million pixels. It's not likely to go into volume production soon, and there isn't any content to display on it, says Paul Semenza, a senior analyst at Display Search. But at last month's Society for Information Display conference in Los Angeles, the display drew crowds and garnered a best-in-show award.

Samsung is the latest TV manufacturer to demonstrate a technology that uses a type of backplane—the array of transistors used to switch the pixels on and off—based on metal oxide semiconductors. These materials offer higher performance than the amorphous silicon widely used today, without increasing costs. In April, manufacturer Sharp announced it will begin manufacturing displays based on metal oxide transistor arrays by the end of the year at its plant in Kameyana, Japan.

It wouldn't have been possible to make the ultra-high-definition display using a conventional backplane, says Sangheon Kenneth Koo, director of LCD marketing at Samsung Semiconductor. That's because making the pixels smaller requires making each of the controlling transistors smaller, too. And the amorphous silicon used in conventional backplanes doesn't conduct electrons fast enough for this kind of miniaturization.

Metal oxide semiconductors conduct electrons very rapidly, and they can be deposited using relatively inexpensive methods. The hurdle has been figuring out which mixtures of metals to use and how exactly to work with them on today's equipment, says Randy Hoffman, a senior engineer at HP. The leading material is now a mixture of indium, gallium, and zinc called IGZO.

Semenza speculates that Sharp might be planning to take advantage of the high pixel densities enabled by metal oxide backplanes to make crisper mobile displays. Based on the size of the equipment at the company's Kameyana production line, he speculates that the company may be aiming to provide a high-resolution tablet display, perhaps for the next generation of Apple's iPad. "The high-water mark for this," says Semenza, "is the retina display" in the latest iPhone, which uses an expensive backplane based on another form of silicon transistor called low-temperature polysilicon. Metal oxide transistor arrays are less expensive to make and provide the necessary performance. Sharp might be able to offer a very good performance alternative to the retina display at a lower price, says Semenza.

Volume manufacturing of metal oxide backplanes could also be a boon for richly colored, energy-efficient organic light-emitting diode displays (OLEDs). These displays have been incorporated into some mobile devices and small high-end televisions, but they tend to be expensive. Part of the problem is that they can't be made with conventional backplanes: the high currents needed for these devices burn out amorphous-silicon transistors. So, OLED makers have been using the expensive polysilicon backplanes. Replacing those with metal oxide backplanes could make OLEDs more competitive.

Other qualities of metal oxides will be attractive in future display technologies, says HP's Hoffman. Every layer in a display tends to absorb some light and decrease overall efficiency and brightness. But metal oxides are transparent, so displays with these backplanes should get more light out and operate more efficiently. Hoffman expects this to be a particular advantage in reflective displays. HP is working on a flexible display that integrates a metal oxide backplane with a full-color reflective display.

Stimulating the brain: Neural activity in the brain of a Parkinsonian rat before (top) and after (bottom) electrical stimulation is applied to its spinal cord. The stimulus elicited a flood of excitatory (red) and inhibitory (blue) neural responses.
Credit: Romulo Fuentes

BIOMEDICINE

Safer Electrical Therapy for Parkinson's

Delivering electrical stimulation via the spinal cord could help ease symptoms of the disease.

Delivering electrical stimulation to the spinal cord through tiny, platinum electrodes could ease the severe motor deficits of Parkinson's disease as effectively as a much more intrusive procedure currently in clinical use, according to a new study in rodents. If the findings are confirmed in humans, scientists say, the procedure could dramatically improve treatment for the disease by making electrical therapies safer and more broadly available.

Parkinson's is a neurodegenerative disorder that develops when the brain cells that produce, excrete, and reabsorb a neurotransmitter called dopamine mysteriously begin to die. Patients initially develop muscle tremors; in the later stages of the disease, their limbs go rigid, and their movements slow to a painful crawl. The disease can be treated by replacing dopamine with a drug called levodopa, or L-dopa, but the drug loses its effectiveness over time. When drugs fail, patients often turn to an invasive surgical treatment called deep brain stimulation, which uses an electric pacemaker to send pulses to very specific areas of the brain. Thousands of Parkinson's patients have received the brain implants to date.

Researchers at Duke University accidently came upon the idea of stimulating the spinal cord as a possible treatment for Parkinson's. While examining rats engineered to exhibit symptoms characteristic of Parkinson's, they noticed that groups of neurons in two areas of the brain, the cortex and the basal ganglia, were firing synchronously. The rhythmic activity was reminiscent of the mild, continuous seizures seen in patients with epilepsy. "I had seen this a decade ago," says Miguel Nicolelis, a professor of neurobiology and codirector of the Center for Neuroengineering at Duke University. At the time, Nicolelis and his collaborators were searching for ways to disrupt rhythmic seizures by stimulating peripheral nerves.

Nicolelis reasoned that a similar approach might work for Parkinson's. So he and his student Romulo Fuentes took their dopamine-depleted mice and rats and attached tiny platinum electrodes to the base of their spinal cords. "When we stimulated them with a small current, we got an effect that was identical--and even better--than what people get when they do this deep brain stimulation," Nicolelis says. The Parkinsonian animals' slow stiff movements were replaced with healthy mouse and rat behaviors.

When Nicolelis and Fuentes combined the electrical stimulation with L-dopa, the effects were even more startling. The electric pulses, combined with only 20 percent of the typical drug dose, resulted in a long-term effect that mimicked L-dopa therapy without appearing to replicate the drug resistance that normally builds up over time. The research was published yesterday in the journal Science.The implant itself is a much easier surgery than the one used for deep brain stimulation, with much lower risk of side effects. The device is relatively superficial, placed right under the vertebrae on the surface of the spinal cord. "It's a very easy, semi-invasive procedure," Nicolelis says. "In the future, we may be able to do this noninvasively, because there are ways you can actually pass currents through skin and through bone to get these fibers excited." Nicolelis plans to test the treatment in chimpanzees before initiating human trials. At least one spinal-cord stimulation therapy is already in clinical use to treat chronic pain. 

While deep brain stimulation has changed the landscape for late-stage Parkinson's treatment, it's still a very complicated, expensive, and deeply invasive procedure, saysPatrick Aebischer, president of the Swiss Federal Institute of Technology, in Lausanne. "If you could do this in humans, it would be a fantastic step," he says, making electrical stimulation available to a much wider group of patients. A noninvasive device would be even more appealing: "If you could do this transcutaneously, you'd change the whole ball game," Aebischer says. "It opens up a very interesting new possibility for using electrophysiology to treat Parkinson's disease."

However, the research is in its early days. "We have to keep in mind that these are experimental data," says Alim Benabid, a professor emeritus of biophysics at Joseph Fourier University, in Grenoble, France, who created the deep brain stimulation technique in the late 1980s. "It is too early to say whether this could replace levodopa treatment or the current deep brain stimulation." But Benabid is already looking at adding spinal-cord stimulation in his next set of trials, paired with another kind of deep brain stimulation (that of the subthalamic nucleus) in patients with "frozen gait" disorder, who have trouble walking.

Nicolelis isn't sure how the therapy works, but he believes that by targeting the spinal column--where huge bundles of fibers are responsible for carrying tactile information from the body to multiple targets in the brain--he and his colleagues are creating electrical current that influences dynamics of the whole neural circuit, rather than just a single spot in the brain. "Parkinson's is a disease of neuronal timing," he says. "My gut feeling is that this works because it desynchronizes these neurons in the motor cortex and the basal ganglia and other locations. This desynchronizes them, gets them out of phase--almost like it introduces a little bit of noise in the system."

In focusing on the spinal cord, Nicolelis says, "we're looking at a very interesting shift in the way you approach the disease. We're approaching it from a systemic point of view, looking at a whole circuit and gaining access to the whole circuit." The scientists are now looking to see whether starting spinal stimulation in combination with L-dopa early on could slow or even prevent the progression of disease.

Liquid Battery (Donald Sadoway conceived of a novel battery that could allow cities to run on solar power at night.)

Conventional battery: Ordinary batteries use at least one solid active material. In the lead-acid battery shown here, the electrodes are solid plates immersed in a liquid electrolyte. Solid materials limit the conductivity of batteries and therefore the amount of current that can flow through them. They’re also vulnerable to cracking, disintegrating, and otherwise degrading over time, which reduces their useful lifetimes.
Credit: Arthur Mount

TR10: Liquid Battery

Donald Sadoway conceived of a novel battery that could allow cities to run on solar power at night.

Without a good way to store electricity on a large scale, solar power is useless at night. One promising storage option is a new kind of battery made with all-liquid active materials. Prototypes suggest that these liquid batteries will cost less than a third as much as today's best batteries and could last significantly longer.

The battery is unlike any other. The electrodes are molten metals, and the electrolyte that conducts current between them is a molten salt. This results in an unusually resilient device that can quickly absorb large amounts of electricity. The electrodes can operate at electrical currents "tens of times higher than any [battery] that's ever been measured," says Donald Sadow­ay, a materials chemistry professor at MIT and one of the battery's inventors. What's more, the materials are cheap, and the design allows for simple manufacturing.

The first prototype consists of a container surrounded by insulating material. The researchers add molten raw materials: antimony on the bottom, an electrolyte such as sodium sulfide in the middle, and magnesium at the top. Since each material has a different density, they naturally remain in distinct layers, which simplifies manufacturing. The container doubles as a current collector, delivering electrons from a power supply, such as solar panels, or carrying them away to the electrical grid to supply electricity to homes and businesses.

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Discharged, charging, charged: The molten active components (colored bands: blue, magnesium; green, electrolyte; yellow, antimony) of a new grid-scale storage battery are held in a container that delivers and collects electrical current (left). Here, the battery is ready to be charged, with positive magnesium and negative antimony ions dissolved in the electrolyte. As electric current flows into the cell (center), the magnesium ions in the electrolyte gain electrons and form magnesium metal, which joins the molten magnesium electrode. At the same time, the antimony ions give up electrons to form metal atoms at the opposite electrode. As metal forms, the electrolyte shrinks and the electrodes grow (right), an unusual property for batteries. During discharge, the process is reversed, and the metal atoms become ions again.
Credit: Arthur Mount

As power flows into the battery, magnesium and antimony metal are generated from magnesium antimonide dissolved in the electrolyte. When the cell discharges, the metals of the two electrodes dissolve to again form magnesium antimonide, which dissolves in the electrolyte, causing the electrolyte to grow larger and the electrodes to shrink (see above).

Sadoway envisions wiring together large cells to form enormous battery packs. One big enough to meet the peak electricity demand in New York City--about 13,000 megawatts--would fill nearly 60,000 square meters. Charging it would require solar farms of unprecedented size, generating not only enough electricity to meet daytime power needs but enough excess power to charge the batteries for nighttime demand. The first systems will probably store energy produced during periods of low electricity demand for use during peak demand, thus reducing the need for new power plants and transmission lines.

Many other ways of storing energy from intermittent power sources have been proposed, and some have been put to limited use. These range from stacks of lead-acid batteries to systems that pump water uphill during the day and let it flow back to spin generators at night. The liquid battery has the advantage of being cheap, long-lasting, and (unlike options such as pumping water) useful in a wide range of places. "No one had been able to get their arms around the problem of energy storage on a massive scale for the power grid," says Sadoway. "We're literally looking at a battery capable of storing the grid."

Since creating the initial prototypes, the researchers have switched the metals and salts used; it wasn't possible to dissolve magnesium antimonide in the electrolyte at high concentrations, so the first prototypes were too big to be practical. (Sadowa­y won't identify the new materials but says they work along the same principles.) The team hopes that a commercial version of the battery will be available in five years. 

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Keeping Neurons Alive in Parkinson's Patients

Keeping Neurons Alive in Parkinson's Patients

An upcoming clinical trial will attempt to solve problems that have plagued one potentially promising treatment.

Targeted treatment: These MRI images of a monkey's brain show a three-dimensional reconstruction of fluid infusions (shown in red and yellow) into the putamen (shown in green and blue)—an area of the brain involved in Parkinson's disease.
Credit: Adrian Kells

A molecule that has long been a source of hope as a potential Parkinson's disease therapy will get a new chance to show its benefit. A team led by Krystof Bankiewicz at the University of California, San Francisco, plans a clinical trial of an experimental gene therapy using glial-derived neurotrophic factor (GDNF), a protein that helps keep neurons alive. The team is in the final stages of gaining approval from the U.S. Food and Drug Administration, and hopes its trial can address issues that marred previous trials.

Current Parkinson's treatments control symptoms, but they don't slow the disease's progression. GDNF first showed promise as a treatment for Parkinson's patients when scientists discovered that it could boost the survival of dopamine-producing neurons—cells that degenerate in the disease—back in 1993. But so far, the results in humans have not borne out those hopes. Early trials involving injecting the protein directly into the brain showed some promise, but a second, more comprehensive trial subsequently showed no benefit. Another recent trial that used a gene therapy approach to deliver a similar compound, neurturin, showed some signs of benefit but failed in its primary goal of improving symptoms after one year.

Bankiewicz believes that other attempts failed because they didn't target the right tissue precisely enough. The first attempts, he said, injected the GDNF protein into the spaces near the brain regions of interest, where it failed to diffuse far enough into the brain. Infusing the treatment directly into the relevant brain tissue, he says, caused leakage into the surrounding fluid. "They all turned out to be negative, because the delivery was never controlled," Bankiewicz says.

The new trial will introduce the gene encoding GDNF into the putamen, a brain area involved in Parkinson's disease. The gene will be carried by a virus, and will be injected directly into the brain using a technique called convection-enhanced delivery, which uses positive pressure to drive fluid deep into targeted regions. The injection will include an MRI contrast agent, and the researchers will use an MRI-based imaging system to track the distribution of the treatment during delivery. Bankiewicz says the imaging system will allow the team to make sure the gene gets to where it's needed.

Once incorporated into cells, the gene would drive the expression of GDNF protein; Bankiewicz says it should then travel to other areas of the brain affected by disease, transported along axons, the long tails of neurons that connect brain regions.

It remains to be seen whether a more precise delivery system is the answer, and scientists disagree over which factors need improvement: the vector that contains the genes, the delivery system, the targeting of relevant brain regions, the types of patients that are studied—or even the gene itself. Andrew Feigin, a neuroscientist at North Shore University Hospital, says that the recent setback in the neurturin trial casts doubt on whether a similar approach will work with GDNF. "It still remains to be seen whether GDNF really is something that helps people with Parkinson's disease," he says.

Ronald Mandel, a neuroscientist at University of Florida, is also working on a GDNF gene therapy. He's optimistic that GDNF could help Parkinson's patients, but he believes it should be tested in patients at the early stages of the disease—before the dopamine-producing cells have become severely diseased and die off. Getting approval to test therapies in such patients, however, is very difficult.