High-Resolution Multi-Scale Computational Model for Non-Invasive Cervical Vagus Nerve Stimulation

Mourdoukoutas, Antonios P.; Truong, Dennis Q.; Adair, Devin; Simon, Bruce J.; Bikson, Marom

doi:10.1111/ner.12706

Cited by 73 publications

(54 citation statements)

References 94 publications

(116 reference statements)

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“…Due to the clinical nature of this study, the target engagement of the cervical vagus nerve could not be validated directly. This study relies on previous literature that reported the ability to reach the vagal afferents using tcVNS [46,47]. We replicated the stimulation application reported in Ref.…”

Section: Limitationsmentioning

confidence: 53%

“…While fewer studies exist focused on tcVNS, several important results have been demonstrated. Imaging studies noted vagal afferents are accessible with tcVNS [46] and, recently, a multi-scale image-derived model of tcVNS was developed predicting the fiber activation due to tcVNS [47]. The downstream effects were observed in serum cytokines, chemokines, and cardiac vagal tone [48,49].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Background: Stress is associated with activation of the sympathetic nervous system, and can lead to lasting alterations in autonomic function and in extreme cases symptoms of posttraumatic stress disorder (PTSD). Vagal nerve stimulation (VNS) is a potentially useful tool as a modulator of autonomic nervous system function, however currently available implantable devices are limited by cost and inconvenience. Objective: The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to stress. Methods: Using a double-blind approach, we investigated the effects of active or sham tcVNS on peripheral cardiovascular and autonomic responses to stress using wearable sensing devices in 24 healthy human participants with a history of exposure to psychological trauma. Participants were exposed to acute stressors over a three-day period, including personalized scripts of traumatic events, public speech, and mental arithmetic tasks. Results: tcVNS relative to sham applied immediately after traumatic stress resulted in a decrease in sympathetic function and modulated parasympathetic/sympathetic autonomic tone as measured by increased pre-ejection period (PEP) of the heart (a marker of cardiac sympathetic function) of 4.2 ms (95% CI 1.6e6.8 ms, p < 0.01), decreased peripheral sympathetic function as measured by increased photoplethysmogram (PPG) amplitude (decreased vasoconstriction) by 47.9% (1.4e94.5%, p < 0.05), a 9% decrease in respiratory rate (À14.3 to À3.7%, p < 0.01). Similar effects were seen when tcVNS was applied after other stressors and in the absence of a stressor. Conclusion: Wearable sensing modalities are feasible to use in experiments in human participants, and tcVNS modulates cardiovascular and peripheral autonomic responses to stress.

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Section: Limitationsmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Firstly, we did not directly corroborate the successful stimulation of the vagus nerve. As nVNS mainly stimulates afferent vagal fibers, 55 heart rates are not useful to confirm successful nVNS. 16,56 However, previous results strongly suggest that cervical nVNS indeed activates vagal afferents.…”

Section: Discussionmentioning

confidence: 99%

A Randomized Sham‐Controlled Cross‐Over Study on the Short‐Term Effect of Non‐Invasive Cervical Vagus Nerve Stimulation on Spinal and Supraspinal Nociception in Healthy Subjects

Alt¹,

Wach²,

Liebler

et al. 2020

Headache

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Objective The aim of the present study was to test the effects of vagus nerve stimulation (VNS) on the descending pain inhibition, quantified by the nociceptive flexor (RIII) reflex and the conditioned pain modulation (CPM) paradigm, and on supraspinal nociceptive responses, assessed by pain intensity and unpleasantness ratings and late somatosensory evoked potentials (SEPs), in healthy subjects. Background Non‐invasive vagus nerve stimulation (nVNS) showed promising effects on headache and pain treatment. Underlying mechanisms are only incompletely understood but may include the activation of the descending pain inhibitory system and/or the modification of emotional responses to pain. Methods Twenty‐seven adult, healthy, and pain‐free subjects participated in this double‐blind cross‐over study conducted at a university research center. They received 4 minutes of cervical nVNS or sham stimulation in randomized order. RIII reflexes, pain ratings, and SEPs were assessed before, during, and 5, 15, 30, and 60 minutes after nVNS/sham stimulation, followed by CPM testing. The primary outcome was the nVNS effect on the RIII reflex size. Three subjects were excluded after the preparatory session (before randomization), 1 subject was excluded after outlier analysis, leaving 23 for analysis. Results RIII reflex areas were 917.1 ± 563.8 µV × ms (mean ± SD) before, 952.4 ± 467.4 µV × ms during and 929.2 ± 484.0 µV × ms immediately after nVNS and 858.4 ± 489.2 µV × ms before, 913.9 ± 539.7 µV × ms during and 862.4 ± 476.0 µV × ms after sham stimulation, revealing no differences between the immediate effects of nVNS and sham stimulation (F [3,66] = 0.67, P = .574). There also were no effects of nVNS over sham on RIII reflex areas up to 60 minutes after nVNS (F [1.7,37.4] = 1.29, P = .283). Similarly, there was no statistically significant effect of nVNS on pain intensity ratings and thresholds, RIII reflex thresholds, late SEP amplitudes, and the CPM effect, compared to sham. Pain unpleasantness ratings statistically significantly decreased from 4.4 ± 2.4 (NRS 0‐10) to 4.1 ± 2.5 during nVNS compared to sham stimulation (F [1,22] = 8.74, P = .007), but there were no longer lasting effects (5‐60 minutes after stimulation). Conclusions The present study does not support an acute effect of nVNS on descending pain inhibition, pain intensity perception or supraspinal nociception in healthy adults. However, there was a small effect on pain unpleasantness during nVNS, suggesting that nVNS may preferentially act on affective, not somatosensory pain components.

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“…Our findings suggest a central action on the specific cortical areas generating the late vertex complex and especially the P2 wave. This effect was obtained with a not nociceptive stimulation, as the conventional cervical nVNS protocols cannot activate a-delta or C-fibers ( Mourdoukoutas et al, 2018 ). These fibers input could thus interfere with the a-delta afferent volley elicited by laser stimulation, by inhibiting late responses at cortical level.…”

Section: Discussionmentioning

confidence: 99%

Effect of Non-invasive Vagus Nerve Stimulation on Resting-State Electroencephalography and Laser-Evoked Potentials in Migraine Patients: Mechanistic Insights

Vecchio

Bassez

Ricci

et al. 2018

Front. Hum. Neurosci.

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A recent multicenter trial provided Class I evidence that for patients with an episodic migraine, non-invasive vagus nerve stimulation (nVNS) significantly increases the probability of having mild pain or being pain-free 2 h post-stimulation. Here we aimed to investigate the potential effect of nVNS in the modulation of spontaneous and pain related bioelectrical activity in a subgroup of migraine patients enrolled in the PRESTO trial by using resting-state electroencephalography and trigeminal laser-evoked potentials (LEPs). LEPs were recorded for 27 migraine patients who received active or sham nVNS over the cervical vagus nerve. We measured power values for frequencies between 1–100 Hz in a resting-state condition and the latency and amplitude of N1, N2, and P2 components of LEPs in a basal condition during and after active or sham vagus nerve stimulation (T0, T1, T2). The P2 evoked by the right and the left trigeminal branch was smaller during active nVNS. The sham device also attenuated the P2 amplitude evoked by the left trigeminal branch at T1 and T2, but this attenuation did not reach significance. No changes were observed for N1 amplitude, N1, N2, P2 latency, or pain rating. nVNS induced an increase of EEG power in both slow and fast rhythms, but this effect was not significant as compared to the sham device. These findings suggest that nVNS acts on the cortical areas that are responsible for trigeminal pain control and pave the ground for future studies aimed at confirming the possible correlations with clinical outcomes, including the effect on symptoms that are directly correlated with trigeminal pain processing and modulation.

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High-Resolution Multi-Scale Computational Model for Non-Invasive Cervical Vagus Nerve Stimulation

Cited by 73 publications

References 94 publications

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

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

A Randomized Sham‐Controlled Cross‐Over Study on the Short‐Term Effect of Non‐Invasive Cervical Vagus Nerve Stimulation on Spinal and Supraspinal Nociception in Healthy Subjects

Effect of Non-invasive Vagus Nerve Stimulation on Resting-State Electroencephalography and Laser-Evoked Potentials in Migraine Patients: Mechanistic Insights

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