Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation

Abstract

a b s t r a c tBackground: The therapeutic potential of transcutaneous auricular VNS (taVNS) is currently being explored for numerous clinical applications. However, optimized response for different clinical indications may depend on specific neuromodulation parameters, and systematic assessments of their influence are still needed to optimize this promising approach. Hypothesis: We proposed that stimulation frequency would have a significant effect on nucleus tractus solitarii (NTS) functional MRI (fMRI) response to respiratory-gated taVNS (RAVANS). Methods: Brainstem fMRI response to auricular RAVANS (cymba conchae) was assessed for four different stimulation frequencies (2, 10, 25, 100 Hz). Sham (no current) stimulation was used to control for respiration effects on fMRI signal. Results: Our findings demonstrated that RAVANS delivered at 100 Hz evoked the strongest brainstem response, localized to a cluster in the left (ipsilateral) medulla and consistent with purported NTS. A colocalized, although weaker, response was found for 2 Hz RAVANS. Furthermore, RAVANS delivered at 100 Hz also evoked stronger fMRI responses for important monoamine neurotransmitter source nuclei (LC, noradrenergic; MR, DR, serotonergic) and pain/homeostatic regulation nuclei (i.e. PAG). Conclusion: Our fMRI results support previous localization of taVNS afference to pontomedullary aspect of NTS in the human brainstem, and demonstrate the significant influence of the stimulation frequency on brainstem fMRI response.

Transcutaneous Auricular Vagal Nerve Stimulation and Disorders of Consciousness: A Hypothesis for Mechanisms of Action

“…As expected, locus coeruleus activation was reported in five out of the seven studies (81-83, 85, 86). Three studies showed an activation of the raphe nuclei following taVNS, either contralateral to the stimulation (82) or bilaterally (85,86), while Badran et al reported no difference (84). Altogether, the studies that analyzed the brainstem with an appropriate protocol (82,83,85,86) supported the activation of the lower and upper brainstem, thereby confirming our hypotheses.…”

“…Stimulation delivered at 100 Hz resulted in a significant increase in the fMRI signal in all targeted brainstem nuclei (ipsilateral periaqueductal and ambiguous nuclei in addition to the nuclei described in the Table 1) compared to no stimulation. Significant differences were also reported at 2 Hz, but only in the dorsal raphe and the contralateral locus coeruleus (86).…”

“…Spinal trigeminal nucleus and tractus of the solitarius nucleus have been reported in four and five fMRI studies, respectively. Three studies supported the activation of the spinal trigeminal nucleus (82,85,86) while one did not report any difference in this structure (84). Activation of the tractus of solitarius nucleus was identified in four studies (82,83,85,86) whereas no change was measured by Badran et al (84).…”

“…Seven studies on healthy subjects have been selected (79)(80)(81)(82)(83)(84)(85)(86). Stimulation parameters and methodological approaches were very heterogeneous and are summarized in Table 1.…”

“…Finally, another research group focused on taVNS' brainstem effects (85,86). The authors matched stimulation with the respiratory cycle and stimulated patients during the inhalation or the exhalation phase on two different fMRI runs.…”