Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects
are not well understood, particularly in humans. We employed ultrahigh field (7T)
fMRI and evaluated the influence of respiratory phase for optimal targeting, applying
our respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique.
We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation
in response to taVNS stimuli would be enhanced when stimulation is delivered during
a more receptive state, i.e. exhalation. Brainstem fMRI response to auricular taVNS
(cymba conchae) was assessed for stimulation delivered during exhalation (eRAVANS)
or inhalation (iRAVANS), while exhalation-gated stimulation over the greater auricular
nerve (GANctrl, i.e. earlobe) was included as control. Furthermore, we evaluated cardiovagal
response to stimulation by calculating instantaneous HF-HRV from cardiac data recorded
during fMRI. Our findings demonstrated that eRAVANS evoked fMRI signal increase in
ipsilateral pontomedullary junction in a cluster including purported NTS. Brainstem
response to GANctrl localized a partially-overlapping cluster, more ventrolateral,
consistent with spinal trigeminal nucleus. A region-of-interest analysis also found
eRAVANS activation in monoaminergic source nuclei including locus coeruleus (LC, noradrenergic)
and both dorsal and median raphe (serotonergic) nuclei. Response to eRAVANS was significantly
greater than iRAVANS for all nuclei, and greater than GANctrl in LC and raphe nuclei.
Furthermore, eRAVANS, but not iRAVANS, enhanced cardiovagal modulation, confirming
enhanced eRAVANS response on both central and peripheral neurophysiological levels.
7T fMRI localized brainstem response to taVNS, linked such response with autonomic
outflow, and demonstrated that taVNS applied during exhalation enhanced NTS targeting.