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

Area of Science:

• Neuroscience
• Neuromodulation

Background:

• Transcranial electrical stimulation (tES) is typically viewed as a direct cortical intervention.
• Evidence suggests tES may have broader effects beyond direct cortical stimulation.

Purpose of the Study:

• To propose an integrated dual-route framework for understanding tES mechanisms.
• To explain inconsistencies in tES research and suggest improved methodologies.

Main Methods:

• Synthesis of human and animal evidence.
• Analysis of tES effects on cortical and peripheral nerve pathways.

Main Results:

• tES co-stimulates cranial and cervical nerves, particularly the trigeminal and greater occipital nerves.
• These nerves engage deep brainstem neuromodulatory nuclei (locus coeruleus, raphe).
• Transcutaneous pathways contribute significantly to tES effects, alongside direct cortical polarization.

Conclusions:

• An integrated dual-route model (cortical + transcutaneous neuromodulation) better explains tES outcomes.
• This model addresses spatial specificity paradoxes, low-intensity effects, and sham inconsistencies.
• Revised control conditions are needed to account for both direct cortical and transcutaneous stimulation routes for enhanced therapeutic efficacy.