You are at a conference, out to dinner with colleagues in the hotel dining room. Mid-conversation, you freeze with the fork halfway to your mouth. Your hands are shaking and you can't hold your head up. The next thing you remember seeing is a paramedic standing over you asking, "What is your name? Do you know where you are?" Your head is full of thoughts but the few words you get out are garbled beyond recognition.
The next morning, you are still weak and foggy-brained, remembering only bits and pieces of what happened.
What happened, explains Jessica Gordon, was an epileptic seizure her first major episode and the one that led to her being diagnosed in 2008 with a partial complex seizure disorder.
Gordon, a 32-year-old Penn State alumna and registered dietician, is one of two million Americans with epilepsy. She believes that the head injury she sustained in a serious car accident in 1996 is responsible for her condition.
It ís possible, say her neurologists, but they're quick to point out that this is a disorder with dozens of contributing causes ranging from genetics, brain tumors and viral infections, to overmedication, Alzheimer's disease and birth trauma. Pinpointing the exact cause is often difficult and sometimes impossible.
Getting a solid diagnosis can also prove tricky. The disease ís most common symptom"loss or impairment of consciousness"can be caused by so many other factors that physicians often take a watch-and-wait approach.
With over forty different types of epilepsy in the medical literature, this disease is more accurately understood as a group of syndromes with distinct symptoms, all involving episodes of abnormal electrical activity in the brain. How do you outsmart a foe you can barely define?
Frederic Weber
Bruce Gluckman (left) and Steven Schiff
With tremendous determination, patience, and the collaboration of many people, says Steven J. Schiff.
Schiff, director of the two-year old Penn State Center for Neural Engineering, professor of Neurosurgery, and Brush Chair Professor of Engineering, trained as a pediatric neurosurgeon and still scrubs in to the operating room once a week at Penn State Hershey Medical Center. He has spent decades researching the physics of nervous system disorders, particularly epilepsy, the spasticity of Cerebral Palsy, and Parkinson's disease.
His challenge since being recruited by Penn State in 2006 is nothing less than assembling and leading one of the most interdisciplinary bioengineering collaborations in the nation, with the common goal of contributing significantly to the next generation of brain-computer interface technologies.
Risk versus Benefit
The need for new solutions almost always arises from frustrations with today's limits. In the case of epilepsy, only one-third of patients' seizures can be "well controlled" using anticonvulsant drugs, explains Schiff; in another third, the epilepsy can be "reasonably controlled." (Even in these cases, such drugs are "far from ideal," he notes, "because they influence every cell in the brain and have a tendency to affect cognition and produce a host of side effects.")
A full third of all patients have what is termed "pharmacologically intractable epilepsy." For this last group, the primary treatment offered is surgical resection (removal) of the damaged lesions within the brain, usually within the hippocampus, an area associated with learning and memory.
"There is always the potential hazard that the part of the brain you're cutting into is not going to function well again," says Schiff. "There is almost no part of the brain that is not serving some useful function," he emphasizes. "For example, when the temporal lobes are resected, there is some decrement in verbal memory if the left side is operated on, and in spatial memory if the right side is operated on."
Jessica Gordon echoes the concerns of many patients when she says, "Given the chance that undergoing brain surgery would not be effective, combined with the potential complications, Iím not choosing a surgical resection route."
More Rational Therapies
The future of seizure treatment—and perhaps the treatment of brain and behavioral disorders in general—belongs to electrical-stimulation therapies, believes Schiff.
This stimulation is delivered by means of a thumbnail-sized computer chip—akin to a pacemaker for the brain—that sends tiny jolts of electrical current applied to specific neural targets. The goal? To block abnormal electrical patterns and stop the symptoms of disease—seizures, spasticity, tremors—before they happen.
Frederic Weber
The procedure, called deep brain stimulation or DBS, involves surgically implanting electrodes into targeted areas of the patient’s brain, along with a small battery. To date, almost 40,000 Parkinson’s patients have undergone DBS surgery, with mixed results. While many patients experience a welcome reduction of their tremors and rigidity, there are side effects for some, including involuntary movements, insomnia, anxiety and depression. Says Schiff, there’s still too much trial and error in choosing and calibrating the pattern and amplitude of the implants’ electrical signals, and that ultimately limits the treatment’s success in reducing a broader range of the disease’s symptoms.
"What we’re striving for in the Center," he adds emphatically, "is the development of more rational ways of interacting with the brain electrically."
A Productive Partnership
Bruce Gluckman emphatically agrees. Associate professor of Engineering Science and Mechanics and of Neurosurgery, Gluckman has been Schiff's primary research partner for over fifteen years.
Together, these two scientists each with different and complementary strengths are intent on the same goals: to find more sensitive, precise and individualized strategies to monitor brain activity and suppress seizures before they strike, and to shape the Center into a pioneering player in the growing field of neural engineering.
Gluckman, casual and outgoing, is essentially a physicist and self-described experimentalist. His primary expertise is in "the group dynamics of individual systems," with an emphasis on the interaction between theoretical ideas and experimental results, and how to apply what is learned directly to models of neural systems.
"My role in the Center is more in day-to-day operations in the lab, where I'm focused on instrument development," he adds.
The instrument in question is the Center's main though by no means only focus: a prototype of the next generation of human brain implant device, based on neurological research on the brains of rats. "I think we're about five years away from a new epilepsy implant and we're working on one for Parkinson's as well," Gluckman says with obvious excitement. "We just have to make sure we can get the bugs worked out first."
Schiff—soft-spoken and intense—is clinically oriented in his research approach, says Gluckman, referring to his partner's drive to address health-related questions, but he adds that Schiff is excellent at building the interdisciplinary bridges both within the Center and between the Center and a diverse network of scientists around the world.
"By combining our skills, I think we've been able to do some very unique things," Schiff says, "with the emphasis always coming back to finding better solutions for people suffering with brain disorders."
The Body Electric
"The simplest way I can explain how I feel during a seizure," says Jessica Gordon, "is that I am stuck in a moment in time that I cannot get out of. I feel like a machine on pause, and I just want someone to hit the play button."
An important aspect of the Center’s research, says Gluckman, is the quest to understand the neural firing patterns inherent in a healthy brain, in order to piece together what makes that complicated organ—"a three pound wet computer"—malfunction, and determine how to hit the correct "play button" for patients like Jessica.
The brain, for all its complexity and mystery, is essentially an electric circuit, Gluckman explains. Over 100 billion brain cells, neurons, communicate with each other through "wires" called dendrites and axons, at connecting junctions called synapses. With an estimated one quadrillion synapses within the human brain, the normal functioning brain provides a constant flow of data to its own neural circuitry, enabling it to make adjustments in its electrical firing through a continuous process of reevaluation and readjustment.
"In healthy brains, there are a host of mechanisms for keeping the network stable," he notes. "They involve combinations of excitatory and inhibitory neurons. When input comes in to a layer, there's a balance between the neurons that want to fire off and the ones that tell the others not to fire too often."
"One could say that temporal lobe epilepsy arises from malformations or miswiring in the hippocampus," he adds. "That's why this part of the brain is a major target for surgical resection. Our objective is to create a prosthetic, a control system, that will sense the instability in the hippocampus that precedes a seizure and reroute the network before the patient experiences cognitive deficits."
Would such an advance replace surgical resection as the treatment of choice for intractable patients? "That's the objective," Gluckman says, nodding. "Itís as if thereís an electrical chain reaction that gets set off in the hippocampus and we're trying to interrupt it before it gets started."
"Broadly speaking," adds Schiff, "we are asking the question " How do you sense that a nervous system is not functioning properly, that its rhythms are wrong, and how can you readjust those rhythms by stimulation?"
Loops and Frequencies
The Center for Neural Engineering is currently comprised of three connected laboratories on the third floor of the Earth-Engineering Sciences Building, on the west end of the University Park campus. In one of those labs, Schiff, Gluckman and colleagues are building and fine-tuning small implantable electronic chips that record the firings of single neurons under low frequency electrical stimulation.
"Low frequency" may be key in taking the guesswork out of choosing the best electrical pattern and amplitude for implanted devices, believe Schiff and Gluckman. Unlike the high frequency current (defined as above 100 Hz, or 100 cycles per second) most often used in neural stimulation, they are working with cycles under 100 Hz--"what we call polarizing low frequency electrical fields, or PLEF" clarifies Gluckman. After years of research with hippocampal brain slices and implanted animals, they've determined that very low frequency current--which creates a constant field lasting longer than the firing of a single neuron allows them to shift the normal "set point" of brain cells. In turn, this modulates the way cells respond to input. In short, adds Schiff, "we can make neurons less responsive to the electrical bombardment of a seizure."
Of equal importance, the two researchers have also discovered that they can simultaneously record electrical activity within the brain during treatment as they adjust response. In effect, a closed loop system is created, allowing them to create "continuous feedback control devices" that interact with the seizures and automatically refine the level of stimulation as needed.
Frederic Weber
Bruce Gluckman in a Center lab
This, explains Gluckman, is a big step toward the more rational implantable device they're seeking a device that could someday evolve into an even more sophisticated brain-computer interface, in which signals passing back and forth from the brain to the computer would in effect, train both.
Says Schiff, with evident hopefulness, "We're pushing the envelope in developing what should be the next generation of closed loop systems."
In October 2009, the National Institutes of Health gave the Center's work a vote of confidence, and a financial boost, when they awarded Penn State a million dollar Biomedical Core Center grant for the Center for Neural Engineering entitled: “Innovations at the Intersection of Neural Engineering, Materials Science and Medicine."
Control and Chaos
If you talk to neural engineers for more than a few minutes, you can expect two words to pop up repeatedly: control and chaos. These are the shorthand names of two principles of physics and engineering used to create models of brain behavior.
The electrical behavior of the brain's neurons, explains Schiff, is a physical system governed by the same laws of "nonlinear dynamics" that apply to planetary systems, meteorology, and even dripping faucets.
Better known as chaos theory, the idea is that small, even almost imperceptible, changes in a system's conditions can lead to radically differing outcomes. This "sensitive dependence" is sometimes referred to as "the butterfly effect," based on the notion that the beating of a butterfly's wings on one side of the world could cause a tornado on the other side.
Chaotic systems, whether the brain's neural firings or the drips from a leaky faucet appear to be random and intrinsically unpredictable, a researcher's worst nightmare.
Yet advancements in mathematical modeling reveal something startling: underlying the apparently chaotic behavior in nonlinear systems, there are predictable organizational patterns.
"The behavior of tens of thousands of neurons in a brain slice is really complex," says Gluckman, with a grin. "But when we analyze their activity with computational modeling, it looks much simpler than what you might expect."
Can successful neural engineering devices be built based on data from computational models? "Control-engineering principles—such as those used in modern aerospace engineering—can be applied to neuroscience," maintains Schiff. "I think the Boeing 777 was the first airplane almost entirely developed from physical and mathematical models on computers. They didn't have to test-fly different versions of the airframe they could do it in computation. And when they finally built it, it flew—and it flew well."
"Of course, all of biology and my aerospace friends may roll their eyes at this but all of biology is much, much, much more complicated than something as simple as an airplane," says Schiff. "We don't know nearly as much about brains to make use of our engineering knowledge. Nevertheless, we are beginning to take that engineering knowledge over to a variety of diseases of the brain."
Bridging the Disciplines
Corina Drapaca is the newest member of the Center. An assistant professor of Engineering Science and Mechanics, she has a Ph.D. in mathematics, and is a specialist in computational mechanics, medical image analysis, and has particular interest in mechanical brain diseases such as hydrocephalus and Chiari malformations. Says Schiff, "She embodies the core disciplinary expertise of Engineering Science and Mechanics and translates this to a better understanding of brain disease and improving treatment."
Looking ahead, Schiff, Gluckman, and their Penn State colleagues--including Drapaca, Jian Xu, Andrew Webb, Francesco Costanzo, and Sulin Zhang, among others--will have plenty of opportunities to build bridges between neuroscience and other disciplines such as engineering, materials science and nanotechnology, just for starters.
In 2011, the Center for Neural Engineering will relocate to a custom-designed 22,000 square-foot facility in the new Materials/Life Sciences complex, under the governance of the Huck Institutes of Life Sciences. The new location will have room for about fifteen faculty members, some of whom will be drawn from within the University. "And we're also vigorously recruiting people who will be new to Penn State," Schiff adds.
One goal: better assistive devices for patients who canít use their bodies well anymore. "Hershey has a very, very impressive A.L.S. clinic [Lou Gehrig's disease]," notes Schiff. "We're working well in our current temporary laboratories, he adds, "but we look forward to having even more sophisticated facilities for optical imaging, high-energy laser research, whole animal research, and labs for behavioral testing and monitoring."
Space for a Brain-Machine Interface teaching lab is already reserved in the building plans. "In the future," says Schiff, "we are going to have a course where our students play neural ping pong as one of the laboratory exercises. We want to guide students into projects that lead into the unknown."
Frederic Weber
The Center will be located near both the Materials Research Institute and the Center for Infectious Disease Research, a proximity Schiff calls "crucial to what we'll be able to do here that's unique at Penn State. We have, arguably, one of the best materials research programs in the world," he continues, "and we want to exploit that knowledge. The neural devices we're creating have to survive in the brain for decades. We need to devise materials that, very gently, can pass electricity into the biological organ without generating toxic chemicals or passing too much current, which can burn a hole in the brain. We need batteries that can last a lifetime, recharged perhaps by the body's own activity. These things are hard to do, but we feel it is extremely important to develop effective and safe neural prosthetic devices. We will make sure the devices developed at Penn State are known for extensive research and development into safety."
Better neural devices will eventually mean that the surgical process of implanting them will become much less invasive, believes Schiff, adding that they could be placed on the surface of the brain, rather than deep within it. That would be welcome news for patients like Jessica Gordon. "Nanotechnology and neural implants are fascinating," she says, "but I like to hope that some day there will be options other than invasive surgery."
For Jessica, things are looking better lately. After an adjustment of her medication, she has gone without a single seizure for eleven weeks. A recent EEG showed improvement and she looks forward to resuming her career as a nutritionist. "I have been able to start running again," she says, "and I am hoping to be able to run in a marathon within one year of my diagnosis. Life is one present moment after another; some are wonderful and others are painful. 'This too shall pass' is a phrase I've learned to repeat quite frequently," she says.
Decreasing those painful times for patients with neurological disorders is what still drives Schiff and Gluckman. "I went into neuroscience because it's the last frontier," says Schiff. Lightly touching his fingers to his head, he adds, "The brain is the one thing we really don't understand. In years to come, I want to look back at what we've accomplished at the Center for Neural Engineering and be able to say, "We didn't rush things, we didn't focus on making a splash in the media or making money from new inventions. We did it carefully and most importantly, we did it right."
Steven J. Schiff, MD, Ph.D., is Brush Chair Professor of Engineering and director of the Penn State Center for Neural Engineering. He can be reached at sjs49@engr.psu.edu. Bruce J. Gluckman, Ph.D., associate professor of Engineering Science and Mechanics, is associate director of the Penn State Center for Neural Engineering. He can be reached at brucegluckman@psu.edu. Corina Drapaca, Ph.D., assistant professor of Engineering Science and Mechanics, can be reached at csd12@psu.edu.