The response clamp: functional characterization of neural systems using closed-loop control

The voltage clamp method, pioneered by Hodgkin, Huxley, and Katz, laid the foundations to neurophysiological research. Its core rationale is the use of closed-loop control as a tool for system characterization. A recently introduced method, the response clamp, extends the voltage clamp rationale to the functional, phenomenological level. The method consists of on-line estimation of a response variable of interest (e.g., the probability of response or its latency) and a simple feedback control mechanism designed to tightly converge this variable toward a desired trajectory. In the present contribution I offer a perspective on this novel method and its applications in the broader context of system identification and characterization. First, I demonstrate how internal state variables are exposed using the method, and how the use of several controllers may allow for a detailed, multi-variable characterization of the system. Second, I discuss three different categories of applications of the method: (1) exploration of intrinsically generated dynamics, (2) exploration of extrinsically generated dynamics, and (3) generation of input–output trajectories. The relation of these categories to similar uses in the voltage clamp and other techniques is also discussed. Finally, I discuss the method's limitations, as well as its possible synthesis with existing complementary approaches.