Multivariate information theory uncovers synergistic subsystems of the human cerebral cortex

One of the most well-established tools for modeling the brain is the functional connectivity network, which is constructed from pairs of interacting brain regions. While powerful, the network model is limited by the restriction that only pairwise dependencies are considered and potentially higher-order structures are missed. Here, we explore how multivariate information theory reveals higher-order dependencies in the human brain. We begin with a mathematical analysis of the O-information, showing analytically and numerically how it is related to previously established information theoretic measures of complexity. We then apply the O-information to brain data, showing that synergistic subsystems are widespread in the human brain. Highly synergistic subsystems typically sit between canonical functional networks, and may serve an integrative role. We then use simulated annealing to find maximally synergistic subsystems, finding that such systems typically comprise ≈10 brain regions, recruited from multiple canonical brain systems. Though ubiquitous, highly synergistic subsystems are invisible when considering pairwise functional connectivity, suggesting that higher-order dependencies form a kind of shadow structure that has been unrecognized by established network-based analyses. We assert that higher-order interactions in the brain represent an under-explored space that, accessible with tools of multivariate information theory, may offer novel scientific insights.