“…Analytical methods for deriving optimal control signals traditionally use calculus of variations 24 – 26 ; broad application of these techniques to biology is limited because validated mathematical models are available in only a few systems, and variational solutions to complex models can be elusive 27 , 28 . To deal with complex models, researchers have used phase reduction models 28 – 32 , parameterized stimuli 33 , or simpler conceptual models 24 , 25 . The majority of biological systems however, do not have models readily available, and as such empirical approaches have explored the system’s responses to simple stimulus waveforms (e.g., rectangular, sinusoidal) 34 – 37 .…”