In the 1780s the Italian physician Luigi Galvani noticed that the legs of dissected frogs twitched when they were touched with metal instruments, or when a spark jumped nearby. He concluded that living tissue produces and responds to electricity. He was right in spirit, though it took another century and a half to learn how nerves actually do it. This level follows a single signal from the moment a nerve cell is stirred to the moment it passes the message along.

Separate cells, not a web

In the late 1800s the Italian scientist Camillo Golgi invented a silver stain that turned a few nerve cells black against a clear background, so that their full branching shape could be seen for the first time. Golgi believed the nervous system was one continuous fused network, like the pipes of a city's water supply. The Spanish anatomist Santiago Ramón y Cajal used Golgi's own stain and drew a different conclusion: the nervous system is made of separate cells that touch but do not fuse. This became known as the neuron doctrine. The two men shared the Nobel Prize in 1906 and used their lectures to disagree with each other. Electron microscopes in the 1950s showed tiny gaps between neurons and settled the matter largely in Cajal's favor.

A charged membrane

Every neuron is a small battery. Its thin outer membrane separates two salty fluids with different mixtures of charged particles, called ions. Pumps in the membrane push sodium ions out and pull potassium ions in, at the cost of a large share of the brain's energy budget. The result is that, at rest, the inside of a typical neuron is about 70 millivolts more negative than the outside. This is the resting potential, and it is what gives the cell something to discharge.

The action potential

Scattered through the membrane are ion channels, tiny protein gates that open and close. When input to a neuron pushes the voltage near the start of its axon past a threshold, sodium channels snap open. Sodium rushes in, and for about a millisecond the inside of the cell becomes positive. Potassium channels then open, potassium flows out, and the voltage drops back. This brief reversal, the action potential or "spike," triggers the same reversal in the next patch of membrane, and so it travels down the axon like a flame along a fuse.

The action potential is all or none: it either fires at full strength or not at all. A weak stimulus that crosses the threshold produces the same size spike as a strong one. So how does the nervous system tell a gentle touch from a hard press? Mainly by timing. A stronger stimulus makes a neuron fire more often, and it may also recruit more neurons. The code is in the rhythm, not the height, of the spikes.

The details were worked out by the British scientists Alan Hodgkin and Andrew Huxley, who published their account in 1952 and shared a Nobel Prize in 1963. Their key tool was the giant axon of the squid, a fiber nearly a millimeter wide that was big enough to thread a wire electrode inside.

Insulation and speed

A bare axon conducts slowly, perhaps a meter or two per second. Many axons in vertebrates are wrapped in myelin, layers of fatty membrane laid down by glial cells. The myelin is interrupted every millimeter or so by small bare gaps called nodes of Ranvier. Because ions can flow only at the gaps, myelin lets the signal leap from gap to gap, which makes it much faster. The fastest human axons carry signals at more than 100 meters per second, quick enough for a sensation in your toe to reach your brain in a few hundredths of a second.

When myelin is damaged, signals slow, scramble or fail. In multiple sclerosis, the body's own immune system attacks and damages myelin in the brain and spinal cord. Depending on where the damage falls, a person may lose sharpness of vision, strength in a leg, or balance, and symptoms often come and go in episodes. Treatments that calm the immune attack have greatly improved the outlook since the 1990s.

Many poisons and medicines act on the channels themselves. Tetrodotoxin, found in pufferfish, blocks sodium channels, so no action potential can start; a tiny dose can stop the nerves that control breathing.

Worked example: the dentist's numbing shot

Before filling a tooth, a dentist injects a local anesthetic such as lidocaine near a nerve in the jaw. Within minutes the lip and cheek feel thick and dead, yet the patient can still move their face and remains fully awake. What is happening?

Lidocaine is a milder, temporary cousin of the pufferfish toxin. It slips into the sodium channels of nearby axons and holds them shut. The pain receptors around the tooth may still be stimulated by the drill, but the action potential cannot travel past the numbed stretch of nerve, so the message never reaches the brain. As the drug washes away over an hour or two, the channels reopen, spikes pass again, and feeling returns, often with an odd tingling as different fibers come back at different speeds. A single principle, the sodium channel gate, explains both a deadly fish and a routine Tuesday appointment.