Can we construct a model of brain function that enables an understanding of whole-brain circuit mechanisms underlying neurological disease and use it to predict the outcome of therapeutic interventions? How are pathologies in neurological disease, some of which are observed to have spatial spreading mechanisms, associated with circuits and brain function? In this review, we discuss approaches that have been used to date and future directions that can be explored to answer these questions. By combining optogenetic functional magnetic resonance imaging (fMRI) with computational modeling, cell type–specific, large-scale brain circuit function and dysfunction are beginning to be quantitatively parameterized. We envision that these developments will pave the path for future therapeutics developments based on a systems engineering approach aimed at directly restoring brain function.