High frequency electrical stimulation paces fast spiking interneurons and modulates cellular information processing.

High frequency intracranial electrical stimulation is routinely used in the clinic, but its therapeutic mechanisms are unclear. Since most neurons cannot follow fast inputs, high frequency neuromodulation is theorized to disrupt pathological dynamics, therefore creating functional informational lesion. However, fast spiking interneurons (FSIs) fire rapidly and thus may be differentially engaged by high frequency neuromodulation. To understand how intracranial electrical stimulation impacts FSIs and their ability to process inputs, we measured the real-time effect of stimulation using cellular voltage imaging in awake mice. We report that visual cortex FSIs, but not motor cortex ones, are reliably paced by high frequency 140 Hz stimulation, though suppressed by low frequency 40 Hz stimulation. Furthermore, 140 Hz stimulation powerfully reduces the amplitude of visual flicker-evoked FSI responses. Thus, high-frequency neuromodulation leads to brain-region dependent pacing of FSIs and modulates their cellular processing of inputs.