Building a minimum frustration framework for brain functions over long time scales.

The minimum frustration principle (MFP) is a computational approach stating that, over the long time scales of evolution, proteins' free energy decreases more than expected by thermodynamical constraints as their amino acids assume conformations progressively closer to the lowest energetic state. This Review shows that this general principle, borrowed from protein folding dynamics, can also be fruitfully applied to nervous function. Highlighting the foremost role of energetic requirements, macromolecular dynamics, and above all intertwined time scales in brain activity, the MFP elucidates a wide range of mental processes from sensations to memory retrieval. Brain functions are compared with trajectories that, over long nervous time scales, are attracted toward the low-energy bottom of funnel-like structures characterized by both robustness and plasticity. We discuss how the principle, derived explicitly from evolution and selection of a funneling structure from microdynamics of contacts, is unlike other brain models equipped with energy landscapes, such as the Bayesian and free energy principles and the Hopfield networks. In summary, we make available a novel approach to brain function cast in a biologically informed fashion, with the potential to be operationalized and assessed empirically.