Inside the human brain, one region looms largest: the cerebral cortex. From thinking to memory, music to mental illness, the cortex controls much of human behavior. For centuries, explanations of this brain control center have been left to theorists, who have drafted grand ideas and, more recently, visions of neural networks. Today, however, scientists like Rafael Yuste are exploiting the full power of cutting-edge technologies to peer inside the cortex and image its intricate inner workings in detail.

Yuste has pioneered a combination of optical imaging and electrophysiological recording techniques to study patterns of neural activity. He is pursuing a "reverse engineering" strategy to understand the function of the cortical microcircuit, a basic element of cortex architecture. By first unraveling the dynamics of specific cortical microcircuits, and next the interactions between those microcircuits, he hopes to build a better understanding of how the whole cortex works. Along the way, he aims to identify potential drug targets for treating epilepsy, by learning how epileptic seizures race across the cortex.

Early in his career, Yuste found a way to image the movement of calcium—a measure of neuronal activity—in the branching fibers, or dendritic spines, of a neuron. Because these structures are so tiny, they have been inaccessible using traditional imaging tools, but as a postdoctoral fellow at Bell Labs in 1995, Yuste recognized that the newly developed two-photon microscope was the ideal solution. Since then, his team has custom-designed a series of two-photon microscopes for studying neural circuits, which have been duplicated by many labs around the world.

Combining novel imaging techniques with electrical recordings of neural activity allows Yuste to address a central question in neural physiology: How do single neurons read and interpret the signals they receive? In one key approach used in his lab, researchers watch neurons through a microscope while electrically stimulating those cells, as a computer analyzes correlations between different neurons to discover how they are connected.

Most recently, Yuste and colleagues have mapped the spatiotemporal dynamics of spontaneous neural activity—how quickly and far neurons fire off chemical signals—in mature cortical circuits. This work confirmed, in brain tissue, the idea that cortical circuits do not fire in random fashion, but instead follow precise, repeated time patterns. The cortex may be hardwired with precise timing and self-control mechanisms.