EpilepsyUSA08-Issue 5

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The Over-Excited Brain

Heightened Adaptability of Infant Brain Has Double Edge

   A baby’s brain is primed for learning, genetically programmed to rapidly adapt its “wiring” to the environment around it. This heightened flexibility—called plasticity—during a critical window of early infancy is unmatched at any other time in the lifespan and is a central tenet of brain development.

Early infancy also is a time when the incidence of seizures is highest, and increasing evidence from several lines of research suggests that the same mechanisms that make the newborn’s brain super-adaptable may be one reason it is also so vulnerable to seizures. The findings help explain how epilepsy develops in infants compared to adults, and point to possible therapeutic interventions that, unlike most current epilepsy drugs, may actually work in babies.

Too Much of a Good Thing

Epilepsy is sometimes described as a condition in which brain circuits are “over-excited;” a symposium at the 2007 annual meeting of the American Neurological Association in October was focused on this concept. It’s as if the synaptic connections that link groups of brain cells become like high-speed rails, shuttling neural signals at super-fast speeds that overwhelm the system and produce the outward signs of seizures. This view is bolstered by emerging research on “fast ripples,” the highly synchronized patterns of nerve cell firing that can be seen on EEG read-outs of brain activity during a seizure.

 Excitation in the brain is not in and of itself a bad thing; in fact, it’s critical to the everyday functioning of the normal brain. “In order to form new connections, brain cells need to have excitation; they need to be active,” says Frances Jensen, a neuroscientist at Harvard Medical School and Children’s Hospital Boston. “A normal brain cell will allow just enough excitation to do a good job, but not enough to have a seizure.”

What exactly is meant by “excitation?” At a fundamental level, all brain function can be broken down to chemical signaling between individual nerve cells, which link together to form complex pathways among groups of cells. When neurons “fire,” they release a tiny microjolt of electricity that in turn unleashes neurotransmitters, brain chemicals that carry messages to interconnected neurons by latching onto specialized receptors on the cell surface, in classic lock-and-key fashion.

Some neurotransmitters, like GABA, are “inhibitory,” meaning they turn neurons “off ” and prevent them from firing, effectively stopping the nerve signal from being passed along the circuit. Other transmitters are “excitatory”— they activate nerve cell firing. Glutamate is the most abundant excitatory neurotransmitter in the brain.

Each neuron in the brain—and there are roughly 100 billion of them—has different numbers of receptors that can recognize inhibitory vs. excitatory neurotransmitters, and must integrate the signals coming in from all of its receptors to decide whether to fire or stay silent.

This tightly orchestrated balance of inhibition and excitation ultimately shapes the synaptic connections that form the brain’s wiring diagram: neural circuits that are used repeatedly fire repeatedly and get stronger; those that are not used weaken and eventually shrink away. Learning and memory, and everything else the brain does, is based on this interplay.

Extreme Plasticity

The newborn brain is a little learning machine. Babies need to rapidly assimilate a wealth of information from their environments into their brain wiring. In the first year of life, an infant will build more new synapses than it will build over the rest of the lifespan. Because of this, a baby’s brain operates essentially in a state of heightened excitation as a baseline.

“A baby’s brain has very little inherent inhibition, but lots of excitation—for good reasons,” Jensen notes. “Nature has designed the infant brain to be just on the edge of being excited,” she says, so it can adapt swiftly to the world around it. The downside to nature’s design is that the infant’s brain also seems to be just one step over the line from the over-excitation of a seizure. “It’s a double-edged sword,” Jensen says. “Almost anything that goes wrong to the neonatal brain can cause a seizure.”

Jensen is a leading proponent of the idea that epilepsy is “an extreme form of plasticity” in which the same brain mechanisms that make memory and learning possible are somehow co-opted by epilepsy to produce the super-fast, synchronous nerve firing characteristic of a seizure.

Helen Scharfman, a neuroscientist at the Nathan Kline Institute and Columbia University, believes that this kind of “pathological plasticity” is particularly relevant to temporal lobe epilepsy. That’s because the circuits in the temporal lobe, a part of the brain that is critical to learning and emotional processing, requires a high degree of flexibility.

“We need that plasticity in the temporal lobe, but it comes with the risk that if the controls aren’t appropriate, there may be too much plasticity,” Scharfman says. “I think you can explain a lot of the processes that we know are involved in the development of epilepsy by looking at normal plasticity gone awry.”

Unraveling what can go wrong to tip the delicate balance of inhibition vs. excitation over the seizure threshold is now the focus of a number of different research laboratories worldwide. What is becoming clear is that there are many pathways that lead to the same endpoint of an over-excited, seizure-prone circuit. The problem can be one of too much excitation—as in too much activation by excitatory neurotransmitters such as glutamate—or it can be a result of not enough inhibition.

“It works like a seesaw,” Jensen says. “Whether you load the excitation end or diminish the inhibition, it’s still going to result in an imbalance in favor of excitation.”

An Explanation for Drugs’ Ineffectiveness?

Jensen’s research group, in collaboration with Kevin Staley of the University of Colorado Health Sciences Center, has identified a specific piece of the molecular puzzle that appears to help keep the neonatal brain in a state of high excitability by diminishing the inhibitory side of the equation. The work focuses on a molecule called NKCC1, which transports chloride into nerve cells. Chloride is a negatively charged ion that suppresses nerve cell activity; GABA receptors inhibit nerve firing because they let chloride flow into the cell.

In the adult, the chloride transporter NKCC1 is balanced by another molecule that pushes chloride out of cells. But in the baby brain, there is no chloride exporter; nature’s genetic program stipulates that it comes onto the scene later in development, some time after the first year of life. That leaves NKCC1 unopposed in the infant brain, which sets up a situation where chloride is already at such high levels inside the cell that when the GABA receptor opens, there’s no room for more chloride. In fact, chloride “flies out of the cell,” Jensen says, causing a net loss of negative charge that paradoxically excites the cell rather than inhibiting it.

Traditional antiepileptic drugs such as phenobarbital target GABA receptors, activating them in order to increase inhibition and therefore suppress seizure activity. But in the infant brain, because of the “wrong-way chloride channel,” the effect of these drugs is the opposite of what is intended, and they actually cause more excitation. “This begins to explain why conventional anticonvulsant drugs really do nothing to stop neonatal seizures,” Jensen says.

New Use for an Old Drug

It turns out that a drug that’s been on the market for decades as a diuretic may be just the ticket for tamping down the over-excitement that makes the neonate’s brain so seizure-prone. The drug, bumetanide, blocks NKCC1 and therefore keeps chloride levels low inside nerve cells, “allowing cells in the baby brain to look a little more adult-like,” Jensen says. This, in theory at least, should allow drugs like phenobarbital to work in babies the way that they do in adults. Early preclinical research in an animal model of a common type of neonatal seizures has shown promise that bumetanide can do just that.

“Bumetanide enhances the anticonvulsant effect of phenobarbital; it’s acting synergistically to allow phenobarbital to actually work the way it is supposed to,” Jensen says. “So we think this tried and true old-fashioned drug has a new purpose.” Based on these promising preclinical results, a phase 1 clinical trial is being initiated at Children’s Hospital Boston to evaluate the safety of combination therapy with bumetanide and phenobarbital.

The safety of using this combination in babies is “a big caveat,” Jensen says, because it’s possible that overriding nature’s design for keeping the neonatal brain on the edge of excitability could interfere with normal brain development at precisely the time when this development is progressing with rapidity.

“The idea is to block these pathways at a critical time point, not for the life of the person. If we go too far, we could block the normal processes of learning and memory,” Jensen notes. “We have to do it at very gentle levels for very short times.”

Brenda Patoine is a freelance science writer who has been covering neuroscience for more than 15 years.