Finding new ways to calm storms in the brain

When Dennis D. Spencer, M.D., a tall, soft-spoken man with an Iowa drawl and a mostly gray beard, speaks about his many colleagues in the Yale Epilepsy Program (YEP), he lists name after name, but always comes back to the word “team.” Much like the interdependent cells of the brain, YEP members all play roles vital to the success of the group as a whole. And the parts fit together very well: throughout its 42-year history, the program has been a leader in the field.

Dennis Spencer, chair and Harvey and Kate Cushing Professor of Neurosurgery, is the YEP’s surgical director, and his wife, Susan S. Spencer, M.D., professor of neurology and neurosurgery, directs the program’s medical side. The program’s two halves are a synergistic marriage in which neurological research centered on the causes, nature and treatment of epilepsy enables further surgical advances, and vice versa.

Founded in 1967 at the Veterans Administration Hospital in West Haven, Conn. (now the VA Connecticut Healthcare System), the YEP has evolved and expanded as the scientific and medical understanding of epilepsy and its causes has broadened. Yale’s team—which now includes more than 20 faculty from the Departments of Neurology, Neurosurgery, Neurobiology and Diagnostic Radiology—has pioneered a number of advances widely viewed as milestones in the field (see “Covering All the Bases”).

Epilepsy is a chronic neurological disorder, affecting about 50 million people worldwide, in which abnormal or excessive activity in the brain’s cortex results in unprovoked seizures. References to epilepsy date back to fifth-millennium B.C. Mesopotamia, when the disorder was thought to have been caused by evil spirits; it was only later that ancient physicians, like Atreya and Hippocrates, began to suspect that seizures originated within the brain.

Most seizures are less than two minutes long, but confusion afterward may last longer. In extreme cases, convulsions may occur. Most cases of epilepsy can be managed, but not cured, with medication. However, in about 20 to 30 percent of patients, seizures cannot be controlled with medications, and about half of these patients are referred for neurosurgical treatment.

One factor critical to the successful neurosurgical treatment of epilepsy is the precise localization of seizure foci; such knowledge enables surgeons to isolate and operate on only those parts of the brain that cause seizures and thereby preserve surrounding normal tissue that supports important neurological functions.

In the late 1960s, Richard H. Mattson, M.D., the YEP’s first director and a leader in the pharmacological treatment of epilepsy, set up closed-circuit television (CCTV) cameras to videotape patients while simultaneously recording their brain activity with electroencephalography (EEG). The two recordings could be easily superimposed to show how behavioral changes correlated with changes in brain activity, a process that would have been quite cumbersome with film technology. Before Mattson’s innovation, people didn’t fully know what seizures looked like within the brain, nor did they fully understand the correlation between brain function and the behavioral aspects of seizures, says Dennis Spencer.

Change was rapid in the early 1970s. It was a time, Spencer says, when “people were breaking away from the concept that you recorded from the scalp with EEG and got kind of a general localization” of seizure activity. As a medical student at Washington University in St. Louis, Spencer had learned to monitor the brain more directly with electrode arrays placed on the dura, a thin, leathery covering of the brain just beneath the skull. On his arrival at Yale as a neurosurgery resident in 1971, Mattson’s CCTV/EEG technique was the main tool for monitoring seizure activity, but Spencer oversaw the replacement of scalp electrodes with intracranial electrodes, both arrays and depth electrodes inserted into the cortex.

Spencer and Yale colleagues soon discerned that most seizures in the brain’s temporal lobe—the most common site of origin for “partial” seizures, those that begin in a localized place—originate in the hippocampus, a structure deep in the brain that plays an important role in managing memory. By more precisely localizing the sources of seizures, Yale neurosurgeons became able to perform surgeries that interrupted seizures but preserved critical functions—especially language and vision—by removing only deeper portions of the brain’s temporal lobe.

Examining the tissue removed during these operations in the mid-1980s, Nihal C. de Lanerolle, D.PHIL., D.SC., now professor of neurosurgery and neurobiology, found abnormalities in levels of the neurotransmitter glutamate, and Jung H. Kim, M.D., now professor emeritus of pathology, found that hippocampi from a majority of epileptic patients had fewer brain cells than those from unaffected people. When Anne Williamson, Ph.D., associate professor of neurosurgery, performed electrophysiological measurements with slices of the removed tissue, she observed electrical changes that correlated with the chemical abnormalities de Lanerolle had observed. Positron emission tomography (PET) studies at Yale revealed lowered glucose metabolism in temporal lobe regions that caused seizures, and magnetic resonance imaging (MRI) showed that the hippocampi of patients with temporal lobe epilepsy were significantly smaller in volume than those in unaffected research subjects.

In the late 1980s the program’s core shifted from the VA Hospital to the medical school campus; soon after, Yale neurologists and neurosurgeons built the epilepsy monitoring unit that Susan Spencer now oversees.

As reflected by the countless stacks of papers lining the shelves in Spencer’s office, neurological research on epilepsy at Yale has been wide-ranging. One Yale-led study, conducted over a 10-year period ending in 2006, prospectively monitored 400 epilepsy patients at seven medical centers in the Northeast U.S. to identify the predictors of different clinical outcomes for temporal lobe epilepsy patients treated with surgery.

“We found that the most important aspect of outcome was control of seizures,” Spencer says. “Even an 85 percent reduction in the number of seizures was not sufficient to improve quality of life. One had to cause complete cessation of seizures.”

Prior to research conducted by Yale neurologists, scientists were unsure how to interpret the EEG recordings produced by the intracranial electrodes Dennis Spencer and others were using. “I’ve been able to study those signals and the way they appear in the context of how they predict surgical outcome, and the kind of tissue pathology that you’ll discover when you do the surgery,” says Susan Spencer.

Much of Susan Spencer’s research focuses on the “network” phenomenon of epilepsy, or the notion that seizure activity in the brain often involves multiple regions, and that understanding how seizures form networks in individual cases has significant implications for treatment—surgical or otherwise.

“‘Network’ is now becoming a buzzword, whereas for awhile it was kind of an unknown,” says Spencer.

Further advances spurred at Yale include the development of a navigation system that precisely directs electrodes to specific areas of the brain, and the design of a membrane that can accompany depth electrodes to gather minute samples of the brain’s neurochemical milieu.

Magnetic resonance physicist R. Todd Constable, Ph.D., uses functional MRI (fMRI), a noninvasive neuroimaging technique that measures neural activity during cognitive or visual tasks, to provide Yale neurosurgeons with similarly important information about the relationship between sites where seizures originate and those areas of the brain that govern functions such as vision and verbal memory. Husband-and-wife team Hoby P. Hetherington, Ph.D., and Jullie W. Pan, M.D., Ph.D., joined the Department of Neurosurgery in 2006, just before the 2007 arrival at Yale of a powerful 7 Tesla (7T) MRI system, one of only about a dozen worldwide.

Hetherington and Pan brought to Yale a wealth of expertise in magnetic resonance spectroscopy (MRS), a technology that can noninvasively create precise chemical profiles of brain tissue. Yale’s 7T system can analyze brain areas as small as three cubic centimeters; in addition to providing valuable information for the treatment of epilepsy, MRS can detect neurochemical changes that may signal the onset of neurodegenerative diseases like Alzheimer’s and multiple sclerosis.

Hal Blumenfeld, M.D., Ph.D., studies how epilepsy interferes with people’s consciousness and ability to think. With fMRI , he can precisely locate brain activity during absence seizures, in which children stare and remain still (see photo, above). But fMRI is prone to artifacts from the body movements that occur during larger seizures, so he complements his fMRI work with single photon emission computed tomography (SPECT). In SPECT, patients are injected with a radioactive tracer just as a seizure begins, allowing imaging to be performed later, when they are no longer moving. The resulting images provide a snapshot of brain activity occurring just after the injection.

In another line of research, Blumenfeld and colleagues reported in 2008 in the journal Epilepsia that an anticonvulsant given early in life can prevent the development of seizures in a mouse model of epilepsy, “the first time it was shown that treatment during development can change the outcome in epilepsy,” he says.

“There are maybe half a dozen other places in the world with the kind of experience we have,” says Susan Spencer, who adds that many cases are referred to the Yale team because they’ve been untreatable elsewhere. “We have highly developed technology to localize those regions generating seizures, and a team of knowledgeable people who continue to do research to advance the field in multiple ways.”

Covering all the bases: the Yale Epilepsy Program