Bridging Higher-Order Information Theory and Neuroimaging: A Voxel-Wise O-Information Framework

The brains functional organization has been extensively studied through pairwise connectivity analyses. While these approaches have provided important insights into brain network organization, they fall short in capturing the complexity of high-order functional interactions (HOI). Particularly relevant is the investigation of redundancy and synergy patterns -not addressable with pairwise interactions-, revealing fundamental mechanisms of brain integration and information processing across various cognitive functions and clinical conditions. Conventional neuroimaging software packages are primarily designed for classical (general linear model-like) analyses but lack native support for HOI metrics. To address this gap, this study introduces a novel framework that bridges high-order information theory with conventional neuroimaging analysis pipelines and is subsequently applied to resting-state functional MRI to demonstrate its practical utility. By representing HOI into voxel-level metrics, our approach allows standard neuroimaging analyses to probe complex multivariate dependencies. Moreover, voxel-level group-comparison analyses show age differences linked with reduced redundancy in default mode network interactions. These findings advance our understanding of the complex relationship between multivariate functional interactions, voxel-level neuroimaging, and behavior, highlighting novel analytic strategies to study high-order information processing underlying cognitive function and its alterations in pathological conditions.