Noninvasive Vagus Nerve Stimulation Alters the Neural and Physiological Response to Noxious Thermal Challenge

Abstract

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n=15 sham and n=15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group × time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group × time × GSR analysis showed a significantly decreased response in nVNS group (p < .0005) in bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.Adding to preclinical work, multiple translational clinical studies also show similar antinociceptive effects of acute (10,(35)(36)(37)(38) and chronic VNS (39).Recent fMRI studies have revealed that nVNS affects brain areas important in pain processing (e.g. the medial thalamus, dorsal ACC, IC, and PFC; (40-43), thus highlighting a potential supraspinal vagal influence on pain perception. Only a single small pilot study (n = 20) has evaluated the neural effects of transcutaneous VNS using auricular "Arnold's nerve" stimulation on experimental pain (36). The results did not show a difference between groups, but a post-hoc analysis of "responders", i.e. subjects (n = 12) with increased pain threshold post-nVNS, showed decreased activation during the application of pain stimuli in the left dorsoposterior insula, ACC, ventromedial PFC, caudate nucleus, and hypothalamus (36). Notably, this study performed continuous transcutaneous auricular VNS during the noxious thermal challenge, possibly confounding the results as emerging literature shows pronociceptive effects during actual VNS, while the antinociceptive effects occur post-VNS (44,45). Taken together, the evidence accumulated to date suggests that VNS alters clinical pain perception, but that VNS must be carefully timed to produce antinociceptive effects. Study objectivesThe objective of this study was to gain a richer understanding of post-nVNS effects on sensory discriminative neurocircuits, affective pain neurocircuits, and the peripheral autonomic response to noxious thermal stimuli. Our goa...

Effects of transcutaneous auricular vagus nerve stimulation at left cymba concha on experimental pain as assessed with the nociceptive withdrawal reflex, and correlation with parasympathetic activity

“…Although NWR has been associated with chronic pain, it is also an experimental acute pain experience and known to increase activity in pain related areas such as those above (Apkarian et al, 2005). tVNS was shown to suppress the activity of these pain related areas in response to painful stimuli (Janner et al, 2018;Lerman et al, 2019). Similarly, in the present study, the taVNS suppressed activity in cortical areas associated with pain perception caused by nociceptive stimulation of the sural nerve, which may have resulted in increased NWR thresholds.…”

“…Plastic changes in the brain can be immediate, such as synaptic activity synchronization, or relatively slow and long lasting, involving a wide range of neural circuits, suggesting that taVNS associated plasticity may also be long lasting, and related to the release of neurotransmitters and analgesic hormones (Beekwilder & Beems, 2010;Oleson, 2002;Sandkühler, 2000). In a previous study using fMRI, taVNS demonstrated sustained activity in cortical areas associated with pain processing for over 10 min (Frangos et al, 2015); moreover, insular cortical activity in response to pain was detected 11 to 17 min after taVNS (Lerman et al, 2019). Short-term taVNS in our study might induce lasting brain plasticity, potentially delaying the activation of pain-processing cortical areas.…”

Cognitive function and brain activation before and after transcutaneous cervical vagus nerve stimulation in healthy adults: A concurrent tcVNS-fMRI study

“…The stimulator (Soterix, 1 × 1tES) was placed on the left cervical VN, which lasted for 8 min and was repeated at a frequency of 25 Hz (24 V for tcVNS, 4.5 V for sham), 2 mA, 0.5 ms pulse width. Previous studies have shown that stimulation of distal cervical locations using low voltage does not result in vagal excitation (Lerman et al, 2019). A 20 V nVNS placed directly on the carotid artery has been shown to activate the VN (Frangos and Komisaruk, 2017;Mourdoukoutas et al, 2018;Klaming et al, 2022).…”

Pain is reduced by transcutaneous cervical vagus nerve stimulation and correlated with cardiorespiratory variability measures in the context of opioid withdrawal

“…In fact, the United States Food and Drug Administration recently cleared tcVNS for acute and preventive treatment of pain associated with most forms of primary headache (28). Recent work has also explored tcVNS effects on noxious stimuli applied peripherally (e.g., leg) (12). This previous study found that participants who were stimulated using a sham device experienced a steady increase in pain scores each time the thermal stimulus was administered.…”

“…Moreover, no pain measurements were reported from the study, though the device was developed to target pain. A more recent sham-controlled study in healthy participants of transcutaneous cervical VNS (tcVNS) found that participants who received sham stimulation experienced a steady increase in pain scores in response to repeated noxious stimuli, while those that received active tcVNS experienced a steady decrease in pain scores (12). The study also identified brain regions that responded differently to active tcVNS compared to sham stimulation-many of which are implicated in pain (13).…”