College of Engineering Magazine- Fall 2000

A Mind Full of Exquisite Machinery

By Taylor McNeill

Picture this: you are playing a drum in sync with another drummer-except you can't see the other drummer and can only hear him with a two-second delay. Yet, somehow, you manage to synchronize your playing. How do you do it?

That's the kind of riddle that John White, an associate professor in the Department of Biomedical Engineering, is trying to solve. Except instead of two drummers, he's studying something far more complex: the brain. "We try to use engineering techniques to understand how microscopic phenomena contribute to patterns of electrical activity in the brain-trying to get at the nuts and bolts of what sorts of events at the molecular level contribute to synchronous patterns of activity."

Take what happens when people-or any mammals, for that matter-learn something new, from linking names and faces of new acquaintances to foraging for food in a new environment. Synchronous activity over long expanses of the brain is involved, White says, particularly in the hippocampal region, the part of the brain critical for the laying down of memory.

By understanding the patterns of electrical activity in this region of the brain, White and his colleagues hope to understand better how the brain works, and understand "what disrupts those patterns in abnormal conditions, like Alzheimer's disease and epilepsy. Our goal is to be able to control epileptic seizures, or to find ways to promote the generation of normal patterns of activity when they start to break down."

At first glance this might be seen as the province of biologists, but as a biomedical engineer, White takes a different tack, using statistical methods and developing new instrumentation to study the problem. One area he's focusing on now is the behavior of ion channels in the fatty membrane of the nerve cells. The membrane acts as an insulator, keeping electrical impulses out, but has very small embedded proteins with channels, or pores, that flicker open and closed. When they open, they allow electrical current, in the form of electrical ions, to pass through the membrane. When that happens, spikes of electrical activity called action potentials travel from one end of the cell to another, essentially transmitting information. "They open and close in a remarkably complex set of events," White says. "It's really exquisite machinery." The ion channels are found on a neuron's dendritic trees, which are the tentacles that extend the neurons' reach, as well as the cell body and axon, the structure by which the cell sends messages to other neurons. "Our hope is that we will understand which populations of ion channels are malfunctioning in epilepsy. And then we would work with pharmacologists or molecular engineers to develop a drug to try to correct that behavior."

While there is no good way to take images of the channels at work, White and his colleagues have developed instrumentation to study individual ion channels. First, they take nerve cells from rats and cultivate individual cells. Keeping these alive in artificial cerebrospinal fluid, they attach a pipette-a very thin piece of pulled glass with a channel running through it-on the nerve cell membrane. Then they establish electrical contact via a salt solution in the pipette, which enables them to measure the electrical current generated by the nerve cells through the ion channels. With that electrical connection in place, they can also create virtual ion channels. A computer generates electrical current and applies it to nerve cells. "With real-time computing techniques, we can use pharmacological agents to block ion channels and replace them with virtual ion channels, and then manipulate the virtual ion channels in any way we like, because they just exist in a computer model."

Ion channels flicker open and closed in a way that seems random. White and his colleagues are studying them "not exactly at the molecular level, but more at the statistical level," he says. He explains: "If you subject a given ion channel to a given stimulus that you expect would make it open, you can't know ahead of time when it's going to open and when it's going to close. The channel flickers open and closed in what appears to be a random manner." It's still unclear whether it's truly random or whether it has some underlying pattern "that we're just not smart enough to see."

All that flickering open and closed has an effect: it generates noise in the neuronal system. White was lead author on a paper published earlier this year in Trends in Neurosciences arguing that the ion channel's opening and closing mechanism serves as a noise source in neurons. The noise, a naturally occurring phenomenon, quite possibly limits how well information is transmitted in the brain. "It seems to be a fundamental property of ion channels, and it's a property that must be accounted for," he says. "We're trying to understand the design principles of the brain. It's a staggeringly difficult problem."

Metal on the Brain

While the hippocampal region is a subject of study because of its key role in forming memories, White focuses on its role in epilepsy, a disorder of electrical activity in the nervous system. In some cases, epileptic activity has been found to be centered in the hippocampal region, such as in the famous case of a patient known as "HM." He had such severe epileptic seizures in the hippocampal region that in the 1950s his doctors removed his hippocampi. The result was startling: no more seizures-and complete anterograde amnesia. HM remembers things from before the surgery, but cannot retain any memories of current happenings.

The hippocampal region has another feature that White finds intriguing: its abundance of zinc. "It's sitting there in synaptic terminals waiting to be released in the hippocampal formation, and that's rare; in most other parts of the brain, the zinc is not there," he says.

White's group and others have shown that there are ion channels specifically affected by zinc. "Typically the zinc jams in the pore and it makes it difficult for sodium, for example, to go through the pore. So we are conducting experiments looking at the potential role zinc may play as a neuro-modulator, changing the excitability of nerve cells," he says.

Nerve cells can be divided into two categories: excitatory neurons and inhibitory neurons. "Excitatory neurons excite their neighbors; when they fire action potentials, they send messages to other nerve cells that encourage them to fire. Inhibitory neurons do the opposite; when they fire, they inhibit firing of their target nerve cells. Epilepsy could be a disruption of the normal inhibitory mechanisms," White notes. "The hypothesis-which we have not yet proven-is that zinc is released under conditions of high excitability, like epilepsy. When zinc is released in those cases, it reduces the excitability." If that's the case, it might be a mechanism the brain uses to keep its activity under control. Because, as White says, "too much activity and you're having a seizure, you're not functioning."

A Head for Engineering

When he started graduate school in biomedical engineering at Johns Hopkins University in 1984, White thought he would build instrumentation and "do things that are a little bit more traditional for engineers. But I got so drawn into the beauty and difficulty of the problem of understanding how the nervous system works that I very quickly decided I wanted to do experiments."

He's been doing them ever since, and at the College of Engineering since 1994. He runs the Neuronal Dynamics Lab, which is part of the Center for BioDynamics. He collaborates with center co-directors Jim Collins and Nancy Kopell, especially in applying techniques of nonlinear dynamics to "understand how populations of nerve cells talk to each other, and how they synchronize or anti-synchronize." One problem they are looking at is how nerve cells that are millimeters apart-pretty far in the brain, with delays of several milliseconds-synchronize, when they can only talk to each other through these delayed circuits.

It's that drumming riddle again: how do you synchronize with delayed information? That's where nonlinear dynamics come in. "We're trying to use and develop techniques for studying nonlinear systems, because the nervous system is fundamentally nonlinear," White says. Perhaps that's the secret to it all: our brains are exquisite nonlinear machines. No wonder they are hard to understand.