Dynamic optical clamp: A novel electrophysiology tool and a technique for closed-loop stimulation

Abstract

Optical methods of neuromodulation show great promise. Recent research has shown that optogenetic and electrical stimulation interact both in vitro and in vivo to facilitate action potentials. With standard electrophysiology approaches, it is not possible to directly compare the cell’s response to a test pulse after an optical or electrical stimulation that lead to the same depolarisation. This paper describes the development of a new “dynamic optical clamp” technique, which aims to build on existing voltage clamp methods, but using light as the clamping input in place of electrical currents. We propose a technique based on combinations of optical and electrical stimulation to clamp membrane potential optically. After illustrating the problem in the context of optogenetically-active spiral ganglion neurons from transgenic mice, the proposed optical clamp was first tested within a NEURON simulation and then demonstrated in vitro with NG108-15 cells transfected with a Channelrhodopsin-2 plasmid. Testing of different control schemes within the NEURON simulation showed that a proportional–integral–derivative controller was appropriate for this application. The dynamic optical clamp technique allowed the membrane voltage of optogenetically-modified NG108-15 cells to be controlled using only light during electrophysiology studies. In order to translate optical approaches into implantable devices, a greater understanding of both the mechanisms of optical modulation and the engineering limitations is desirable. The dynamic optical clamp can be adapted for use in closed-loop neuronal control in future generations of neuroprosthetic devices. The enhanced control afforded by this technique could facilitate future investigations of ion channel dynamics during optical stimulation.