For over a century, scientists have been using electrical stimulation to explore and treat the human brain. The technique has helped identify regions responsible for specific neural functions-for instance, the motor cortex and pleasure center-and has been used to treat a variety of conditions from Parkinson's disease to depression. Yet no one has been able to see what actually happens at the cellular level when the brain is electrically prodded.
Now, with the aid of optical imaging technology, researchers in the lab of HMS neurobiology professor Clay Reid have taken the first look at this process. They found that the neural response to electrical currents isn't localized, as some had previously thought. That is, not all neurons immediately surrounding an electrode fire when a charge is delivered. Rather, a scattered and widely distributed set of neurons switch on. These findings, which will appear in the August 27 issue of Neuron, promise to end a longstanding debate about how neurons react to electrical stimulation.
Traditionally, observing neurons during electrical stimulation has been problematic. First author Mark Histed, a postdoctoral fellow in Reid's lab, explains, "When you are stimulating electrically you are using relatively high voltages, and those high voltages make it almost impossible to record the very small currents that neurons produce."
To sidestep this obstacle, Histed, Reid and postdoctoral fellow Vincent Bonin used a relatively new form of optical imaging called two-photon microscopy. The technique allowed them to track calcium levels in the neurons of mice as they were being exposed to electrical stimulation. When calcium levels increased, a chemical that had been introduced into the tissue brightened. Since calcium levels spike every time a neuron fires, the team could literally see the neurons flash each time they were activated. More importantly, they could monitor which neurons were being triggered.
According to Histed, these findings run counter to a long-standing hypothesis. "One prior theory was that at low currents, the neurons in a tiny ball around the electrode would activate, and if you increased the current, a larger ball would activate, but you would still only activate cells within that ball. What we showed was that, even at the lowest currents, you have cells very far away that are activated, so it's not just a tiny ball around the electrode tip that increases in size, but instead a very large, sparse pattern that fills in as the current is increased."