Simultaneously Excitatory and Inhibitory Effects of Transcranial Alternating Current Stimulation Revealed Using Selective Pulse-Train Stimulation in the Rat Motor Cortex.

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Transcranial alternating current stimulation (tACS) uses sinusoidal, subthreshold, electric fields to modulate cortical processing. Cortical processing depends on a fine balance between excitation and inhibition and tACS acts on both excitatory and inhibitory cortical neurons. Given this, it is not clear whether tACS should increase or decrease cortical excitability. We investigated this using transcranial current stimulation of the rat (all males) motor cortex consisting of a continuous subthreshold sine wave with short bursts of suprathreshold pulse-trains inserted at different phases to probe cortical excitability. We found that when a low-rate, long-duration, suprathreshold pulse-train was used, subthreshold cathodal tACS decreased cortical excitability and anodal tACS increased excitability. However, when a high-rate, short-duration, suprathreshold pulse-train was used this pattern was inverted. An integrate-and-fire model incorporating biophysical differences between cortical excitatory and inhibitory neurons could predict the experimental data and helped interpret these results. The model indicated that low-rate suprathreshold pulse-trains preferentially stimulate excitatory cortical neurons, whereas high-rate suprathreshold pulse-trains stimulate both excitatory and inhibitory neurons. If correct, this indicates that suprathreshold pulse-train stimulation may be able to selectively control the excitation-inhibition balance within a cortical network. The excitation-inhibition balance then likely plays an important role in determining whether subthreshold tACS will increase or decrease cortical excitability.SIGNIFICANCE STATEMENT Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation method that uses weak sinusoidal electric fields to modulate cortical activity. In healthy volunteers tACS can modulate perception, cognition, and motor function but the underlying neural mechanism is poorly understood. In this study, using rat motor cortex, we found that tACS effects are highly variable: applying the same tACS waveform to the same cortical area does not always give the same change in cortical excitability. An integrate-and-fire model incorporating excitatory pyramidal and inhibitory interneurons indicated that tACS effects likely depend on the cortical excitation-inhibition balance. When cortical activity is excitation dominated one particular tACS phase increases excitability, but when the cortical activity is inhibition dominated the same tACS phase actually decreases excitability.