Spatiotemporal recruitment of inhibition and excitation in the mammalian cortex during electrical stimulation

Electrical stimulation has emerged as a powerful and precise treatment in which to modulate aberrant neural activity patterns common in neural dysfunction and disease; however, the physiological process involved in microstimulation is poorly understood, particularly regarding the contributions of inhibitory neurons to shaping stimulation-evoked activity. To address this issue, we used 2-photon imaging of transgenic mice to measure the widespread responses of inhibitory and excitatory neurons to electrical stimulation through a chronically-implanted cortical microelectrode. We found that increasing stimulation amplitude both raised the fraction of neurons that responded to a stimulus and increased the distance at which inhibitory and excitatory neurons were significantly modulated by stimulation; however, the lateral spread of inhibitory activity preceded that of excitatory activity. By 50 {micro}A, a significantly larger fraction of inhibitory neurons vs. excitatory neurons were modulated by stimulation. Increasing amplitude also shifted the temporal response properties of the population -- towards longer-latency excitation close to the electrode tip and strong inhibition of more distant neurons. Animal behavior, specifically their locomotion patterns, strongly correlated with trial-to-trial variability in stimulation-evoked responses. We conclude that changing electrical stimulation amplitude can shift the balance of excitation to inhibition in the brain in a manner that interact with ongoing animal behavior.