Optimal stimulus design for multi-frequency cell membrane capacitance estimation

Electrical measurements of cell membrane capacitance serve as a marker for cell surface area and, hence, are widely used to study stimulus-secretion coupling in a variety of cells. The fundamental goal is to estimate the fractional (fF) changes in baseline capacitance that occur as secretory granules fuse with the cell membrane and subsequently extrude the contents of the vesicle. In order to confidently detect these minute events the authors have developed a method of optimizing the stimulus waveform in order to minimize the variance of the parameter estimates. The optimization process is constrained by the fact that the authors are severely limited in terms of the overall excursion of the voltage waveform that is used to stimulate the cell. They discuss a method for tailoring the waveform, by adjusting the relative magnitude and phase of the individual components of the multi-frequency stimulus, such that the voltage excursion is minimized. Finally, the authors demonstrate that significant improvements are obtainable using multiple frequencies to further customize the stimulus waveform.