From cranium to brain: Rethinking tES neuromodulation through the peripheral pathways.

Transcranial electrical stimulation (tES) is traditionally framed as a purely cortical intervention, and weak direct or alternating currents delivered through scalp electrodes are assumed to modulate excitability or entrain oscillations directly under electrodes. However, a growing body of evidence suggests that this transcranial view is incomplete. We synthesized converging human and animal evidence showing that tES also co-stimulates cranial and cervical nerves, especially branches of the trigeminal and greater occipital nerves, which engage deep brainstem neuromodulatory nuclei, such as the locus coeruleus and raphe. Activation of these transcutaneous pathways can mediate many behavioral and physiological effects attributed to direct cortical polarization. We propose an integrated dual-route framework in which tES outcomes reflect the weighted sum of (i) local electric field effects on the cortex, and (ii) brainstem neuromodulation initiated transcutaneously. This model explains spatial-specificity paradoxes, low-intensity effects, and sham inconsistencies and mandates revised control conditions that mask both routes. Recognizing the transcutaneous contribution not only explains the mixed findings but also introduces new opportunities that can ultimately improve therapeutic efficacy.