Multidimensional frequency domain analysis of full-volume fMRI reveals significant effects of age, gender and mental illness on the spatiotemporal organization of resting-state brain activity Miller, RL, EB Erhardt, EA Allen, AM Michael, JA Turner, J Bustillo, JM Ford, DH Mathalon, TGM van Erp, S Potkin, A Preda, G Pearlson, and VD Calhoun (2015). Frontiers in Neuroscience. 9(203) pdf, 1–19. Online: June 16, 2015 http://journal.frontiersin.org/article/10.3389/fnins.2015.00203/abstract doi: 10.3389/fnins.2015.00203 Abstract Clinical research employing functional magnetic resonance imaging (fMRI) is often conducted within the connectionist paradigm, focusing on patterns of connectivity between voxels, regions of interest (ROIs) or spatially distributed functional networks. Connectivity-based analyses are concerned with pairwise correlations of the temporal activation associated with restrictions of the whole-brain hemodynamic signal to locations of a priori interest. There is a more abstract question however that such spatially granular correlation-based approaches do not elucidate: Are the broad spatiotemporal organizing principles of brains in certain populations distinguishable from those of others? Global patterns (in space and time) of hemodynamic activation are rarely scrutinized for features that might characterize complex psychiatric conditions, aging effects or gender—among other variables of potential interest to researchers. We introduce a canonical, transparent technique for characterizing the role in overall brain activation of spatially scaled periodic patterns with given temporal recurrence rates. A core feature of our technique is the spatiotemporal spectral profile (STSP), a readily interpretable 2D reduction of the native four-dimensional brain × time frequency domain that is still “big enough” to capture important group differences in globally patterned brain activation. Its power to distinguish populations of interest is demonstrated on a large balanced multi-site resting fMRI dataset with nearly equal numbers of schizophrenia patients and healthy controls. Our analysis reveals striking differences in the spatiotemporal organization of brain activity that correlate with the presence of diagnosed schizophrenia, as well as with gender and age. To the best of our knowledge, this is the first demonstration that a 4D frequency domain analysis of full volume fMRI data exposes clinically or demographically relevant differences in resting-state brain function.