A central goal of the BRAIN Initiative is to understand how electrical and chemical signals code information in neural circuits and give rise to sensations, thoughts, emotions and actions. Available technologies for recording and manipulating neural circuit activity in human and animal experiments are not sufficient to accomplish this goal. Non-invasive technologies are low resolution and/or provide indirect measures such as blood flow, which are imprecise. Invasive technologies can provide information at the level of single neurons producing the fundamental biophysical signals, but they can only be applied to tens or hundreds of neurons, out of a total number in the human brain estimated at 85 billion. Previous BRAIN FOAs sought to develop novel technology (RFA-NS-15-003) or to optimize existing technology ready for in-vivo proof-of-concept testing and collection of preliminary data (RFA-NS-15-004). This FOA seeks applications for technology at an even earlier stage of development. It seeks new and untested ideas that are in the very earliest stages. The support provided might enable calculations, simulations, computational models, or other mathematical approaches for demonstrating that the signal sources and/or measurement technologies are theoretically capable of meeting the demands of large-scale recording or manipulation of circuit activity. The support might also be used for building and testing phantoms, prototypes, in-vitro or other bench-top models in order to validate underlying theoretical assumptions in preparation for future FOAs aimed at testing in animal models. Invasive or non-invasive approaches are sought that will ultimately enable or reduce the current barriers to large-scale recording or manipulation of neural activity, and that would be compatible with experiments in humans or behaving animals. Applications are encouraged from any qualified individuals, including physicists, engineers, theoreticians, and scientists, especially those not typically involved with neuroscience research.