When will my next seizure happen? Where will I be? Will I be alone or in public? Will I become unconscious? Incontinent? Will I be hurt if I fall? For a person with seizures, these questions are part of every day. Unpredictability is one of the most devastating consequences of epilepsy.

For neurologists "when and where" translates into the questions: "How often do the patient's seizures occur, and from what part of the brain do they arise?" The answers help determine the best treatment.

For scientists the "when and where" of seizures has another layer of meaning. Gregory Worrell, M.D., Ph.D., and Matt Stead, M.D., Ph.D., two physician-researchers at Mayo Clinic, knew the answer would bring them closer to the "why" of epilepsy — its fundamental cause. Dr. Worrell, a neurologist with expertise in epilepsy and physics, and Dr. Stead, a pediatric neurologist with expertise in electrophysiology and large-scale computing, combined forces in 2002 to pinpoint the exact moment and location of seizure generation.

Their search took them into the microdomains of the living brain, yielding volumes of data far beyond the capacity of humans to analyze. It is the computer cluster and massive data center, humming away in their laboratory, spooling up to100 megabytes of data per second, 350 gigabytes per hour, 8.2 terabytes per day, that makes the analysis possible. But it is the human brain that ultimately makes sense of it. With their colleagues and co-investigators Richard Marsh, M.D., and Fredric Meyer, M.D., in adult neurosurgery and Nicholas Wetjen, M.D., in pediatric neurosurgery, Drs. Worrell and Stead have shown that seizures begin on a microscopic scale, often long before they affect behavior.

Electrical misfiring in the brain

A seizure is an episode of uncontrolled electrical activity in the brain. All brain activity, whether it translates into thought, speech, sensation or movement, is generated by brain cells called neurons. Neurons communicate with each other through electrical signals. Their electrical activity varies, creating irregular and asynchronous wave patterns. During the generation of a focal seizure (those that impact only part of the brain), however, neurons begin to fire in concert and recruit neighboring neurons into the abnormally synchronous pattern. When enough neurons are recruited to this symphony, their uncontrolled discharge translates into symptoms ranging from a brief episode of staring to loss of consciousness and convulsions.

How many neurons does it take?

To detect abnormal electrical activity in the brain, physicians use electroencephalography. Electrodes are attached to the scalp or implanted in the brain. The sum of electrical signals from millions of neurons at each electrode site are transmitted to a machine that displays the waveforms in a visual record called an electroencephalogram (EEG).

A single neuron cannot have a seizure; a seizure requires a population of neurons firing together. But how does it start, and how many neurons does it take? The smallest functional units of the cortex, the part of the brain from which measurable seizures arise, are arrangements of cells called cortical columns. Each column is a network of neurons dedicated to a specific function. Measuring an average of just 300 microns across (the width of perhaps four human hairs), each column is made up of only 1,000 to 7,500 neurons. To put that in perspective, a standard intracranial electrode records from an area approximately 10 millimeters square and captures the activity of thousands of cortical columns and millions of neurons. Clearly, EEG machines are not designed to probe the microscopic microdomains within the brain.

Creating investigative tools

To discover if seizures originate in a single cortical column, Drs. Worrell and Stead would need to find a totally new way to record human neuronal activity. First, they would need microelectrodes, only 40 microns in diameter, smaller than a neuron and thinner than human hair. Because they wanted to capture individual neuron activity as well as the rhythmic activity from populations of neurons generating a wide range of oscillations from hundreds of locations, they would need to dramatically expand the recording capability of standard EEG. Their equipment would have to have hundreds of channels capable of recording frequencies over 10,000 Hz. And, because seizures occur infrequently, they would need to record over several days. And to acquire, store and analyze the vast amount of data, they would need a system with massive storage and computing power.

To turn their idea into reality required investment from Mayo Clinic, multiple epilepsy foundations and the National Institutes of Health. A Mayo discovery grant got them started. The acquisition system, computer cluster and data server were built in collaboration with Neuralynx Inc. A unique, first-of-its-kind system capable of recording from over 300 electrodes at 32,500 Hz for days to weeks, it is one of the world's largest data recording acquisition systems. While it was under construction, the scientific and clinical team, including neurosurgeons Drs. Marsh, Meyer and Wetjen, was assembled.

Mapping the brain

As part of the research protocol, the neurosurgeons implant microelectrode arrays along with standard clinical EEG electrodes during brain-mapping surgery. Brain-mapping is a technique to distinguish normal brain tissue from the areas that give rise to seizures — called the epileptogenic zone. After electrodes are surgically implanted, patients undergo continuous EEG recording for days at a time in the intensive care unit (ICU). When enough seizures have been recorded to map the epileptogenic zone, that part of the brain is removed in a second operation.

Microseizures are alive!

The team's first attempts yielded little usable data. It took considerable refinements to filter out the electrical "noise" in the ICU and to improve data acquisition, transmission, compression and analysis. Yet, the eureka moment came one night in 2007 when Drs. Worrell and Stead saw what looked like synchronous activity coming from an area the size of a single cortical column.

Dr. Stead explains, "Just a half-millimeter away, all the microelectrodes surrounding that column were quiet. There was no seizure activity." The next day when the pattern was repeated from the same patient in a different cortical region, Dr. Worrell called out, "Microseizures are alive!" Dr. Stead rushed over to witness the first confirmed evidence that seizure activity occurs in humans in the smallest unit of functional brain organization. Since that time, the team has recorded hundreds of microseizures in patients in areas within and outside of the epileptogenic zone. They have discovered that microseizures are sparsely distributed, more frequent in brain regions that generate seizures, and sporadically evolve into clinical seizures. Rare microseizures are even observed in patients without regular seizures, but not on a scale that characterizes epilepsy.

The Mayo findings suggest that the genesis of epilepsy involves abnormal microdomains of brain tissue which generate microseizures. A clinical seizure may arise when a critical volume of synchronous microdomain activity is reached. This confirmation adds to the evidence that seizures may begin well before they produce observable symptoms and long before they are detected by standard EEG.

What's next?

The Mayo team is now designing a clinic-based prototype of the research EEG machine they use to detect microseizures in the operating room. The new system will improve sensitivity through increased spatial sampling using microelectrode arrays and wide-frequency bandwidth. Microelectrodes could potentially be implanted in a less invasive surgical procedure than used for standard electrodes.

In addition, microseizure recordings could greatly improve precision of brain-mapping and may enable surgeons to both map and remove the epileptogenic zone in a single procedure. If so, the patient would be spared a second surgery and days of EEG monitoring in the ICU. Another possible future application: an implantable early warning device that could alert patients to a potential seizure.

Having identified the microdomain origins of seizure activity, the team is now probing the extracellular space surrounding neurons to determine if chemical alterations there cause microseizures in cortical columns. The answer will provide yet another important step in the origins of focal epilepsy, and seizure generation, prediction and prevention.

— February 2011