The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study

• Published in: Brain stimulation 2019-07, Vol.12 (4), p.911-921
• Main Authors: Sclocco, Roberta, Garcia, Ronald G., Kettner, Norman W., Isenburg, Kylie, Fisher, Harrison P., Hubbard, Catherine S., Ay, Ilknur, Polimeni, Jonathan R., Goldstein, Jill, Makris, Nikos, Toschi, Nicola, Barbieri, Riccardo, Napadow, Vitaly
• Format: Article
• Language: English
• Subjects: Adult; Animals; Brain Stem - diagnostic imaging; Brain Stem - physiology; Electrocardiography - methods; Female; Heart Rate - physiology; Humans; Magnetic Resonance Imaging - methods; Male; Respiratory Mechanics - physiology; Transcutaneous Electric Nerve Stimulation - methods; Vagus Nerve - physiology; Vagus Nerve Stimulation - methods; Young Adult
• ISSN: 1935-861X; 1876-4754
• DOI: 10.1016/j.brs.2019.02.003

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. •Respiration influences the activity of NTS, which is facilitated during exhalation.•The effects of auricular vagus nerve stimulation can be optimized with respiratory gating.•We use 7T fMRI and heart rate variability to investigate central and peripheral responses to tVNS.•Exhalation-gated tVNS enhances engagement of key neuromodulator brainstem nuclei.•Exhalation-gated tVNS increases stimulus-evoked cardiovagal outflow.