Site-specific stimulation imperative: Lessons from a failed auricular-cervical transcutaneous vagus nerve stimulation...

Area of Science:

• Neuromodulation
• Neuroscience
• Biomarker validation

Background:

• Transcutaneous vagus nerve stimulation (tVNS) shows promise for neuromodulation.
• Site-specific effects of auricular (taVNS) and cervical (tcVNS) stimulation are not well understood.
• Lack of understanding complicates clinical protocol selection for tVNS.

Purpose of the Study:

• Directly compare taVNS and tcVNS effects on biomarkers.
• Investigate modulation of heart-evoked potential (HEP), neuro-cardiac coupling (NCC), heart rate variability (HRV), and salivary alpha-amylase (sAA).
• Utilize closely matched, taVNS-optimized parameters for comparison.

Main Methods:

• Within-subject design with 33 healthy adults.
• Stimulation conditions: taVNS, tcVNS, and sham.
• Data collection: electroencephalogram, electrocardiogram, salivary samples, and computational modeling for vagus nerve engagement verification.

Main Results:

• Computational modeling indicated failure to activate the deep cervical vagus nerve with applied tcVNS parameters.
• The tcVNS condition was reclassified as non-specific cervical stimulation (nscES).
• Limited HEP increase observed post-taVNS; no significant effects on NCC, HRV, or sAA. Exploratory analysis showed nscES increased sAA, suggesting non-specific somatic afferent activation.

Conclusions:

• Inability to activate the cervical vagus nullifies direct comparison between taVNS and tcVNS.
• Anatomical depth requires site-specific protocols for accurate cross-site tVNS comparisons.
• Propose a "verify-first" framework for future studies, validating target engagement before physiological comparisons. sAA response to cervical stimulation questions its specificity as a vagus biomarker.