Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients

Abstract

Migraine pathophysiology includes altered brainstem excitability, and recent neuromodulatory approaches aimed at controlling migraine episodes have targeted key brainstem relay and modulatory nuclei. In this study, we evaluated the impact of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel neuromodulatory intervention based on an existing transcutaneous Vagus Nerve Stimulation approach, in the modulation of brainstem activity and connectivity in migraine patients. We applied 3T-functional magnetic resonance imaging with improved in-plane spatial resolution (2.62×2.62 mm) in episodic migraine (interictal) and age- and sex-matched healthy controls to evaluate brain response to RAVANS (gated to either inhalation or exhalation) and sham stimulation. We further investigated RAVANS modulation of tactile trigeminal sensory afference response in the brainstem using air-puff stimulation directed to the forehead during functional magnetic resonance imaging. Compared to sham and inhalatory-gated RAVANS (iRAVANS), exhalatory-gated RAVANS (eRAVANS) activated an ipsilateral pontomedullary region consistent with nucleus tractus solitarii (NTS). During eRAVANS, NTS connectivity was increased to anterior insula and anterior mid-cingulate cortex, compared to both sham and iRAVANS, in migraine patients. Increased connectivity was inversely correlated with relative time to the next migraine attack, suggesting clinical relevance to this change in connectivity. Post-stimulation effects were also noted immediately following eRAVANS, as we found increased activation in putative pontine serotonergic (i.e. nucleus raphe centralis) and noradrenergic (i.e. locus coeruleus) nuclei in response to trigeminal sensory afference. Regulation of activity and connectivity of brainstem and cortical regions involved in serotonergic and noradrenergic regulation and pain modulation may constitute an underlying mechanism supporting beneficial clinical outcomes for eRAVANS applied for episodic migraine.

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

“…However, optimized response for different clinical indications may depend on specific neuromodulation parameters, and systematic assessments of their influence are still needed to optimize the effects of this promising approach. Our study followed up on our previous work demonstrating enhanced brainstem response to taVNS delivered in the cymba conchae of the left ear during the exhalation phase of respiration (RAVANS [4,7,26]), and characterized the brainstem Fig. 3.…”

“…Our own studies have described another, less commonly explored stimulation parameter, respiratory phase of stimulation, finding that stimulation during the exhalatory phase produced more robust NTS, as well as locus coeruleus and raphe nuclei response in the brainstem [7,26]. While Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) has been found to enhance brainstem targeting for taVNS, parameter optimization within this framework with other important stimulus variables, such as burst frequency, are unknown.…”

Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress

“…Brain imaging studies reveal that taVNS devices can modulate the vagal afferents [15,37e39], along with studies that report improved vagal tone through heart rate, heart rate variability, and microneurography [40,41], increased salivary alpha amylase, and decreased salivary cortisol [42]. Beneficial outcomes have been noted by multiple groups on episodic migraine [39], epilepsy seizure frequency [14], major depression [43,44], and chronic tinnitus [45].…”

Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot Study

“…Vagus nerve stimulation (VNS) paired with motor activity enhances neuroplasticity, facilitates cortical reorganization and neurogenesis, and improves motor function post stroke (Porter et al, 2012;Engineer et al, 2015;Dawson et al, 2016). Recently, a noninvasive form of VNS known as transcutaneous auricular VNS (taVNS) targeting the auricular branch of the vagus nerve (ABVN) has demonstrated activation of the vagal afferent and efferent networks (Kraus et al, 2013;Garcia et al, 2017;Yakunina et al, 2017;Badran et al, 2018a,c). In patients with limb impairment post stroke or brain injury, pairing taVNS with motor activation can enhance plasticity and improve functional motor recovery (Dawson et al, 2016;Pruitt et al, 2016;Redgrave et al, 2018).…”