Electrophysiology · Lobeworks/17

Electrophysiology is the branch of physiology that studies the electrical properties of living cells and tissues by measuring, and sometimes imposing, the voltages and currents across their membranes, and it is how almost everything known about the nerve impulse was found.

Electrophysiology. Electrophysiology is the branch of physiology that studies the electrical properties of living cells and tissues by measuring, and sometimes imposing, the voltages and currents across their membranes, and it is how almost everything known about the nerve impulse was found. Its instruments run from a glass pipette sealed onto one patch of membrane to the EEG electrodes on a scalp; what they share is that they read electricity directly, with the timing of the cell itself, where imaging methods such as calcium imaging read a slower chemical echo of it.

A neuron is electrical because its membrane is a charged insulator crossed by ion channels: ions moving through the channels change the charge on the membrane, and with it the voltage. An electrode placed inside the cell, or sealed against its surface, reads that voltage over time (current clamp); an amplifier with feedback can instead hold the voltage at a chosen value and measure the current the cell needs to keep it there (voltage clamp), which isolates what the channels are doing at that voltage. Electrodes outside the cells read the small voltages that their currents leave in the surrounding fluid: one cell's spikes from a fine wire beside it, a crowd's from probes such as Neuropixels, the summed activity of millions from grids on the cortex or the scalp.

It began with frogs. Luigi Galvani reported in 1791 that a frog's leg muscle twitched when metals touched its nerve, and read it as electricity made by the animal, a claim argued over for decades before nerves were shown to carry electrical signals.

The spike was explained with a voltage clamp. Alan Hodgkin and Andrew Huxley held the membrane of the squid giant axon at set voltages and measured the sodium and potassium currents that flowed, five papers in 1952 that gave the mechanism of the action potential and the 1963 Nobel Prize.

The patch clamp reached a single molecule. Erwin Neher and Bert Sakmann sealed a polished pipette onto a few square micrometres of membrane and in 1976 recorded the opening and closing of one channel, a current of picoamperes; the tight gigaohm seal of 1980 made the method general, and the 1991 Nobel Prize followed.

Clinical neurophysiology is the same discipline at the bedside. The EEG, electrocorticography and stereo-EEG read the brain's electricity to find where an epilepsy starts, and every implant that decodes movement or speech is an extracellular recording that runs for years.

It reads the signal at the speed it is sent.

Electrophysiology is the only family of methods that follows neurons at their own timescale, below a millisecond, and the price is reach: the finer the electrode, the fewer cells it hears, and the deeper the target, the more it has to go through skin, bone or brain.

Questions: Why still record with electrodes when calcium imaging can watch thousands of neurons at once? Because the two methods trade the same thing in opposite directions: calcium imaging knows which cell fired, electrodes know exactly when. A calcium indicator brightens and fades over tens to hundreds of milliseconds, so a burst of spikes blurs into one glow and the order of spikes between cells is lost, while an electrode sees each spike as it happens, under a millisecond wide, and a patch pipette even sees the currents below the threshold that never become spikes. An electrode also needs no gene introduced and no window for light, which is why it is the method used in people. Labs that need both put them together: imaging to find the cells, an electrode on a few of them to read their timing.