Beyond Local Gating: Toward Network-State-Dependent Neuromodulation

Brain stimulation is progressively evolving from anatomically targeted interventions toward individualized, adaptive, and network-oriented approaches. Recent developments in brain-state-dependent stimulation have demonstrated that neuromodulation can be optimized by synchronizing stimulation with ongoing neural activity, while adaptive cortico-cortical paired associative stimulation (ccPAS) has extended this principle to distributed cortical networks. However, current approaches continue to define brain state primarily through local electrophysiological features, such as oscillatory phase or power, even though ccPAS is specifically designed to modify communication between interconnected cortical regions. In this opinion paper, we argue that the endogenous variable guiding ccPAS should instead describe the instantaneous physiological state of the targeted cortico-cortical pathway. We propose that online source-space functional connectivity provides a biologically meaningful and technically feasible estimate of this pathway state, thereby enabling a new framework of network-state-dependent neuromodulation. As illustrative applications, we consider pathways spanning different levels of experimental characterization, from established sensorimotor interactions to the less-characterized ventral premotor cortex (PMv)-posterior superior temporal sulcus (pSTS) pathway within the action-observation network (AON). This distinction highlights that the proposed framework is pathway-general, while its experimental implementation requires pathway-specific characterization of stimulation parameters and appropriate physiological readouts. In this framework, resting-state EEG is rapidly reconstructed in source space to estimate pathway connectivity, which is subsequently used to personalize stimulation targets and guide state-dependent ccPAS of a functionally defined cortico-cortical circuit. Finally, we discuss the technological prerequisites, methodological challenges, biological rationale, and open scientific questions that must be addressed before pathway-state-guided neuromodulation can be experimentally validated. We argue that redefining brain state as the instantaneous physiological state of the communication pathway targeted by stimulation may represent the next conceptual step in brain stimulation.