The brain’s structural connectivity supports the propagation of electrical impulses, manifesting as patterns of coactivation, termed functional connectivity. Functional connectivity emerges from the underlying sparse structural connections, particularly through polysynaptic communication. As a result, functional connections between brain regions without direct structural links are numerous, but their organization is not completely understood. Here we investigate the organization of functional connections without direct structural links. We develop a simple, data-driven method to benchmark functional connections with respect to their underlying structural and geometric embedding. We then use this method to reweigh and reexpress functional connectivity. We find evidence of unexpectedly strong functional connectivity among distal brain regions and within the default mode network. We also find unexpectedly strong functional connectivity at the apex of the unimodal-transmodal hierarchy. Our results suggest that both phenomena—functional modules and functional hierarchies—emerge from functional interactions that transcend the underlying structure and geometry. These findings also potentially explain recent reports that structural and functional connectivity gradually diverge in transmodal cortex. Collectively, we show how structural connectivity and geometry can be used as a natural frame of reference with which to study functional connectivity patterns in the brain. Author Summary The structural connectivity of the brain supports interregional signaling, manifesting as highly organized patterns of functional connectivity. Importantly, structural and functional connectivity are fundamentally constrained by the spatial embedding of brain regions, such that proximal regions are more likely to exhibit stronger connectivity. Here we develop a simple method that uses robust relationships between geometry, structure, and function as the baseline to reweigh and reexpress functional connectivity. We use the method to identify functional connections that are greater than expected given their structural and geometric embedding. We then show that the arrangement of these connections systematically follows the functional modules and the putative unimodal-transmodal hierarchy of the brain. Collectively, our findings demonstrate highly organized patterns of polysynaptic functional connections that support the emergence of canonical features of functional connectivity networks, including modules and hierarchies.

The brain is a complex network of interconnected and interacting neuronal populations. Global efforts to understand the emergence of behavior and the effect of perturbations depend on accurate reconstruction of white matter pathways, both in humans and in model organisms. An emerging animal model for next-generation applied neuroscience is the common marmoset ( Callithrix jacchus ). A recent open respository of retrograde and anterograde tract tracing presents an opportunity to systematically study the network architecture of the marmoset brain (Marmoset Brain Architecture Project; http://www.marmosetbrain.org ). Here we comprehensively chart the topological organization of the mesoscale marmoset cortico-cortical connectome. The network possesses multiple nonrandom attributes that promote a balance between segregation and integration, including near-minimal path length, multiscale community structure, a connective core, a unique motif composition, and multiple cavities. Altogether, these structural attributes suggest a link between network architecture and function. Our findings are consistent with previous reports across a range of species, scales, and reconstruction technologies, suggesting a small set of organizational principles universal across phylogeny. Collectively, these results provide a foundation for future anatomical, functional, and behavioral studies in this model organism. Author Summary Emerging research points to network connectivity as a fundamental feature of brains, influencing interregional signaling, cognition, and behavior. Global efforts are under way to map, image, and trace cellular connection patterns in humans and in a variety of model organisms. The common marmoset is increasingly becoming the most used nonhuman primate model for neuroimaging, genomics, and behavioral research. Here we provide a comprehensive characterization of the marmoset brain connectome using a recently published cortico-cortical tract tracing atlas. We find evidence of nonrandom organization across multiple scales, including near-minimal path length, multiscale community structure, densely interconnected hubs, a unique motif fingerprint, and the existence of topological cavities. Collectively, these features suggest that the network is configured to support the coexistence of segregation and integration of information.

Author Summary In the present report we asked how signals travel on brain networks and what types of nodes they potentially visit en route. We traced individual path motifs to investigate the propensity of communication paths to explore the putative unimodal-transmodal cortical hierarchy. We find that the architecture of the network promotes signaling via the hierarchy, suggesting a link between the structure and function of the network. Importantly, we also find instances where detours are promoted, particularly as paths traverse attention-related networks. Finally, information about hierarchical position aids navigation in some parts of the network, over and above spatial location. Altogether, the present results touch on several emerging themes in network neuroscience, including the nature of structure-function relationships, network communication and the role of cortical hierarchies. Abstract The wiring of the brain is organized around a putative unimodal-transmodal hierarchy. Here we investigate how this intrinsic hierarchical organization of the brain shapes the transmission of information among regions. The hierarchical positioning of individual regions was quantified by applying diffusion map embedding to resting-state functional MRI networks. Structural networks were reconstructed from diffusion spectrum imaging and topological shortest paths among all brain regions were computed. Sequences of nodes encountered along a path were then labeled by their hierarchical position, tracing out path motifs. We find that the cortical hierarchy guides communication in the network. Specifically, nodes are more likely to forward signals to nodes closer in the hierarchy and cover a range of unimodal and transmodal regions, potentially enriching or diversifying signals en route. We also find evidence of systematic detours, particularly in attention networks, where communication is rerouted. Altogether, the present work highlights how the cortical hierarchy shapes signal exchange and imparts behaviorally relevant communication patterns in brain networks.