Noninvasive vagus nerve stimulation alters neural response and physiological autonomic tone 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 the nVNS group (p < .0005) 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.

Conflict of interest statement

Bruce Simon PhD has stock/shares in Electrocore LLC. Imanuel Lerman MD MSc carried out prior investigator initiated research that was funded by Electrocore LLC including investigating anti-inflammatory effects of nVNS and neural effects of nVNS measured with MEG. These prior studies do not overlap with this study and Electrocore had no part in this study funding or design. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Noninvasive vagus nerve stimulation study design.

(a) Subjects were screened and randomized to either the sham treatment or nVNS group. Sham stimulation was carried out posteriolateral to the sternocleidomastoid. In the nVNS group, stimulation occurred anteromedial to the sternocleidomastoid and lateral to the trachea. In both the nVNS and sham treatments, a computational fixed, initial 30-second ramp-up period was followed by 90 seconds of peak stimulation. (b) Subjects were allowed to rest for 5 minutes before undergoing 2 minutes of nVNS (electrodes placed over carotid) or sham stimulation (electrodes placed far lateral to the sternocleidomastoid). Subjects then rested for an additional 5 minutes. Nine and a half minutes after either nVNS or sham stimulation, 5 successive noxious thermal stimuli were applied in bouts of 5 seconds each, up to 49.8°C. Each heat stimulus began 110 seconds after the start of the previous one. fMRI, and GSR acquisition were taken 9.5 to 16.8 minutes after nVNS or sham treatment.

Fig 2. nVNS vs sham autonomic measures of sympathetic tone galvanic skin response (GSR) with noxious thermal challenge.

(A) The time to peak galvanic skin response (GSR) measured in seconds after the application of each of the noxious thermal stimuli was significantly reduced in the nVNS group for noxious thermal stimuli 1 and 2 (T1 and T2) (**p < .05) compared with the sham group, and approached significance for T3 and T4 (δp < .09). Mixed-model regression showed that the combined (T1-T5) time to peak GSR in the nVNS group was significantly shorter compared with the sham group (p < .02). (B) The GSR slope (in microsiemens) from the baseline GSR (prior to the application of each noxious thermal stimulus) to the peak GSR (accompanying each noxious thermal stimulus) was measured in each group. The slope from the baseline GSR to the peak response decreased in both groups with each successively applied noxious thermal stimulus from T1 to T3. However, whereas the nVNS group showed a negative average slope to peak GSR of -0.0461 from T3 to T5, the sham group showed a positive average slope to peak GSR of 0.049 from T3 to T5. The between-group difference (group x time interaction = -0.09508) for T3 to T5 was significant at *p < .05. Red circles = nVNS group. Blue circles = sham group.

Fig 3. Group differences in the time course of Blood Oxygen Level-Dependent (BOLD) responses over the entire course of the pain experience.

Imaging of (a) the bilateral somatosensory cortex (SI), and (c) SII, (f) left dorsoposterior insula, (h) bilateral mediodorsal thalamus and dorsal anterior cingulate (area 24), and (k) right media frontal gyrus (orbitofrontal cortex; OFC). Differential hemodynamic response curves during the application of noxious thermal stimuli 10 to 15 minutes following VNS (turquoise) and sham treatments (pink) were generated with a group × time, linear mixed-effects analysis showed that (b) subjects in the sham group had greater activity in the bilateral postcentral gyrus (SI; p = .0006). Treatment with nVNS significantly decreased the response of the postcentral gyrus during and after the application of noxious thermal stimuli (5 seconds each), up to 12 seconds after cessation of the painful stimulus. Subjects in the sham group had greater activity in the bilateral SII (d, e) (mean and SE shown) (right p = .0009, left p = .0009)]. Subjects in the sham group had greater activity in the left posterior insula (g) (mean and SE shown; p = .0004), during and after the application of noxious thermal stimuli (5 seconds each). This result demonstrates blunting of the usual temporal dynamic response of the insula (as seen in the sham group) that is most evident during and up to 10 seconds after cessation of the painful stimulus. The sham group showed significantly greater activity in the medial thalamus and anterior cingulate (area 24) (i, j) (mean and SE shown; mediodorsal thalamus p = .0004, area 24 p = .0004), during and after the application of noxious thermal stimuli (5 seconds each). Subjects in the nVNS group had significantly decreased activity in right middle frontal gyrus (l), overlapping with the medial and lateral OFC (mean and SE shown; p = .0002) followed by an increase in OFC response (greater than sham) that was most evident at the 10 to 15 second mark.

Fig 4. Neural and autonomic measures taken during the application of thermal stimuli (mean GSR, measured from the peak after the application of the thermal stimulus for 15 seconds).

Group (nVNS vs sham) × linear time x GSR linear mixed-effects analysis. (A) Compared with subjects in the nVNS group, subjects who underwent sham treatment showed significantly greater activity in the bilateral somatosensory cortex. (B) Differential hemodynamics of pain following nVNS (turquoise) and sham (pink) treatment. (SI; mean and SE show; p = .0002). (C) Cerebellum/medullary brain stem measures taken during the application of thermal stimuli show (D). To assist in visual representation of this region of interest, the sham and nVNS groups were separated into high and low mean GSRs (using a group median of 16 microsiemens; the high group included 5 subjects who received sham treatment and 7 subjects who received nVNS treatment). (D) Only the high-GSR sham group (pink shade with blue line) demonstrated greater activity in the medulla/brain stem with the application of noxious thermal stimuli. At this medullary level (i.e. the level of the olive from the lower pons, spanning to the lower medulla) multiple afferent fibers enter the brainstem, including the vagus, glossopharyngeal, hypoglossal, and accessory nerves, that synapse on multiple brainstem nuclei [i.e. the nucleus tractus solitarius (NTS), nucleus ambiguous (NAmb), and dorsal motor nucleus of the vagus nerve (DMNX)]. Other brainstem nuclei important for nociception [i.e. the rostral ventrolateral medulla (RVLM), rostral ventromedial medulla (RVM), and nucleus reticularis (Rt)] are also found at this level.