Author Summary Brain stimulation devices capable of perturbing the physiological state of neural systems are rapidly gaining popularity for their potential to treat neurological and psychiatric disease. A root problem is that underlying dysfunction spans a large-scale network of brain regions, requiring the ability to control the complex interactions between multiple brain areas. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. We demonstrate the ability to predictably reconfigure patterns of interactions between functional brain areas by modulating the strength and location of stimulation. Our findings have high significance for designing stimulation protocols capable of modulating distributed neural circuits in the human brain. Abstract Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.

AUTHOR SUMMARY Our ability to thoughtfully engage with the world around us changes appreciably as we transition from childhood to adulthood. Yet, how our brains develop to enable that change remains far from understood. Here we used network science—traditionally applied to the study of social networks like Facebook or Twitter—and machine learning to show that growing cognitive abilities are accompanied by greater flexibility of brain regions within distributed networks. This flexibility is greatest in the executive system, which is critical for higher-order cognitive functions and increases in expression and flexibility from childhood to young adulthood. These results suggest that healthy development is facilitated by an increasing precedence of executive networks and a greater switching of the regions and interactions subserving these networks. Abstract Cognitive function evolves significantly over development, enabling flexible control of human behavior. Yet, how these functions are instantiated in spatially distributed and dynamically interacting networks, or graphs, that change in structure from childhood to adolescence is far from understood. Here we applied a novel machine-learning method to track continuously overlapping and time-varying subgraphs in the brain at rest within a sample of 200 healthy youth (ages 8–11 and 19–22) drawn from the Philadelphia Neurodevelopmental Cohort. We uncovered a set of subgraphs that capture surprisingly integrated and dynamically changing interactions among known cognitive systems. We observed that subgraphs that were highly expressed were especially transient, flexibly switching between high and low expression over time. This transience was particularly salient in a subgraph predominantly linking frontoparietal regions of the executive system, which increases in both expression and flexibility from childhood to young adulthood. Collectively, these results suggest that healthy development is accompanied by an increasing precedence of executive networks and a greater switching of the regions and interactions subserving these networks.