Spontaneous Dynamics Predict the Effects of Targeted Intervention in Hippocampal Neuronal Cultures

ABSTRACT Microstimulation is a powerful tool for causal interrogation of neural circuits and for therapeutic neuromodulation. However, predicting network-level responses to focal perturbations remains a major challenge. To address this problem in a tractable manner, we combine experiments on networks of hippocampal neurons cultured on high-density multielectrode arrays with spiking network model simulations. To characterize spontaneous and stimulation-evoked network dynamics, we employ a combination of direct electrophysiological readouts and information-theoretic measures. We find that single-channel stimulation reliably evokes a small set of site-specific, stereotyped network activity patterns. Remarkably, effective connectivity inferred from spontaneous activity captures the spatial organization of perturbation responses, enabling reliable ranking of stimulation-evoked effects across the network. Our spiking network model reproduces these observations and reveals the interplay between short-term synaptic depression and distance-dependent excitatory and inhibitory connectivity in shaping both spontaneous and evoked interactions at different effective scales. Spontaneous activity involves local structural routes, while perturbation-evoked responses engage comparatively longer, polysynaptic pathways. By unifying in silico modeling with experimental measurements, this work links spontaneous network structure to stimulation-evoked dynamics, suggesting that spontaneous effective connectivity may serve as a tractable proxy for stimulation targeting in recurrent circuits, with potential implications for the rational design of neuromodulatory interventions.