Cervical Vagus Nerve Stimulation Research Articles

Stellate ganglia stimulation counteracts vagal stimulation by significantly increasing heart rate and blood pressure.

Vasovagal syncope (VVS) is the leading cause of syncope. The most frequent mechanism is that of a cardioinhibitory response, vasodepressor response, or mixture of both. Neural stimulation that negates or overcomes the effects of vagal tone may be used as a treatment strategy for VVS. Six male canines were studied. Stimulation (10-Hz, 2ms pulse duration, 2min duration) of the cervical vagus (CV), thoracic vagus (TV), and stellate ganglia (SG) was performed using needle electrodes at 3V, 5V, and 10V output. SG stimulation at an output of 10V overlaying TV stimulation at the same output was performed. Heart rate (HR), blood pressure (BP), and cardiac output (CO) were measured before, during, and after stimulation. Right cervical vagal stimulation was associated with significant hemodynamic changes. HR, SBP, and DBP were reduced (107±16 vs. 78±15bpm [P<0.0001], 116±24 vs. 107±28mmHg [P=0.002] and 71±18 vs. 58±20mmHg [P<0.0001]), respectively, while left cervical vagal stimulation had minimal changes. CV stimulation was associated with greater hemodynamic changes than TV stimulation. Left and right SG stimulation significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR at 5V and 10V, which could be observed within 30s after stimulation. An output-dependent increase in hemodynamic parameters was seen with both left and right SG stimulation. No difference between left and right SG stimulation was seen. SG stimulation overlay significantly increased HR, BP, and CO from baseline vagal stimulation bilaterally. Stellate ganglia stimulation leads to increased HR and BP despite significant vagal stimulation. This may be exploited therapeutically in the management of vasovagal syncope.

Organ- and function-specific anatomical organization of vagal fibers supports fascicular vagus nerve stimulation

Vagal fibers travel inside fascicles and form branches to innervate organs and regulate organ functions. Existing vagus nerve stimulation (VNS) therapies activate vagal fibers non-selectively, often resulting in reduced efficacy and side effects from non-targeted organs. The transverse and longitudinal arrangement of fibers inside the vagal trunk with respect to the functions they mediate and organs they innervate is unknown, however it is crucial for selective VNS. Using micro-computed tomography imaging, we tracked fascicular trajectories and found that, in swine, sensory and motor fascicles are spatially separated cephalad, close to the nodose ganglion, and merge caudad, towards the lower cervical and upper thoracic region; larynx-, heart- and lung-specific fascicles are separated caudad and progressively merge cephalad. Using quantified immunohistochemistry at single fiber level, we identified and characterized all vagal fibers and found that fibers of different morphological types are differentially distributed in fascicles: myelinated afferents and efferents occupy separate fascicles, myelinated and unmyelinated efferents also occupy separate fascicles, and small unmyelinated afferents are widely distributed within most fascicles. We developed a multi-contact cuff electrode to accommodate the fascicular structure of the vagal trunk and used it to deliver fascicle-selective cervical VNS in anesthetized and awake swine. Compound action potentials from distinct fiber types, and physiological responses from different organs, including laryngeal muscle, cough, breathing, and heart rate responses are elicited in a radially asymmetric manner, with consistent angular separations that agree with the documented fascicular organization. These results indicate that fibers in the trunk of the vagus nerve are anatomically organized according to functions they mediate and organs they innervate and can be asymmetrically activated by fascicular cervical VNS.

Parasympathetic control of gastrointestinal motility and cross-branch actions of parasympathetic neuromodulation.

Parasympathetic control of gastrointestinal motility and cross-branch actions of parasympathetic neuromodulation.

Cervical transcutaneous vagal nerve stimulation to improve mission qualification training for an AFSOC full motion video/geospatial analysis squadron

Cervical transcutaneous vagal nerve stimulation to improve mission qualification training for an AFSOC full motion video/geospatial analysis squadron

Transcutaneous vagus nerve stimulation - A brief introduction and overview.

Invasive cervical vagus nerve stimulation (VNS) is approved for the treatment of epilepsies, depression, obesity, and for stroke-rehabilitation. The procedure requires surgery, has side-effects, is expensive and not readily available. Consequently, transcutaneous VNS (tVNS) has been developed 20years ago as non-invasive, less expensive, and easily applicable alternative. Since the vagus nerve reaches the skin at the outer acoustic canal and ear, and reflex-responses such as the ear-cough-reflex or the auriculo-cardiac reflex have been observed upon auricular stimulation, the ear seems well suited for tVNS. However, several sensory nerves with variable fiber-density and significant overlap innervate the outer ear: the auricular branch of the vagus nerve (ABVN), the auriculotemporal nerve, greater auricular nerve, and to some extent the lesser occipital nerve. VNS requires activation of Aβ-fibers which are far less present in the ABVN than the cervical vagus nerve. Thus, optimal stimulation sites and parameters, and tVNS-algorithms need to be further explored. Unravelling central pathways and structures that mediate tVNS-effects is another challenge. tVNS impulses reach the nucleus of the solitary tract and activate the locus-coeruleus-norepinephrine system. However, many more brain areas are activated or deactivated upon VNS, including structures of the central autonomic network and the limbic system. Still, the realm of therapeutic tVNS applications grows rapidly and includes medication-refractory epilepsies, depressive mood disorders, headaches including migraine, pain, heart failure, gastrointestinal inflammatory diseases and many more. tVNS might become a standard tool to enhance autonomic balance and function in various autonomic, neurological, psychiatric, rheumatologic, as well as other diseases.

Differences in the regulatory mechanism of blood flow in the orofacial area mediated by neural and humoral systems.

Marked blood flow (BF) changes mediated by the autonomic neural and humoral systems may be important for orofacial hemodynamics and functions. However, it remains questionable whether differences in the autonomic vasomotor responses mediated by neural and humoral systems exist in the orofacial area. This study examined whether there are differences in changes in the BF and vascular conductance (VC) between the masseter muscle and lower lip mediated by autonomic neural and humoral systems in urethane-anesthetized rats. Electrical stimulation of the central cut end of the lingual nerve elicited BF increases in the masseter (mainly cholinergic) and lower lip (mainly non-cholinergic), accompanied by an increase in arterial blood pressure (ABP), while cervical sympathetic trunk stimulation consistently decreased BF at both sites. The lingual nerve stimulation induced a biphasic change in the VC in the masseter, consisting of an initial decrease and a successive increase. This decrease in VC was positively correlated with changes in ABP and diminished by guanethidine. Cervical vagus nerve stimulation also induced BF increases at both sites; the increases were greater in the masseter than in the lower lip. Adrenal nerve stimulation and isoproterenol administration induced BF increases in the masseter but not in the lower lip. These results indicate that cholinergic parasympathetic-mediated hemodynamics evoked by trigeminal somatosensory inputs are closely related to ABP changes. The sympathetic nervous system, including the sympathoadrenal system and visceral inputs, may be more involved in hemodynamics in the muscles than in epithelial tissues in the orofacial area.

Abdominal vagus nerve stimulation alleviates collagen-induced arthritis in rats.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease. Despite therapeutic advances, a significant proportion of RA patients are resistant to pharmacological treatment. Stimulation of the cervical vagus nerve is a promising alternative bioelectric neuromodulation therapeutic approach. However, recent clinical trials show cervical vagus nerve stimulation (VNS) was not effective in a significant proportion of drug resistant RA patients. Here we aim to assess if abdominal vagus nerve stimulation reduces disease severity in a collagen-induced arthritis (CIA) rat model. The abdominal vagus nerve of female Dark Agouti rats was implanted and CIA induced using collagen type II injection. VNS (1.6 mA, 200 μs pulse width, 50 μs interphase gap, 27 Hz frequency) was applied to awake freely moving rats for 3 h/day (days 11-17). At 17 days following the collagen injection, unstimulated CIA rats (n = 8) had significantly worse disease activity index, tumor necrosis factor-alpha (TNF-α) and receptor activator of NFκB ligand (RANKL) levels, synovitis and cartilage damage than normal rats (n = 8, Kruskal-Wallis: P < 0.05). However, stimulated CIA rats (n = 5-6) had significantly decreased inflammatory scores and ankle swelling (Kruskal-Wallis: P < 0.05) compared to unstimulated CIA rats (n = 8). Levels of tumor necrosis factor-alpha (TNF-α) remained at undetectable levels in stimulated CIA rats while levels of receptor activator of NFκB ligand (RANKL) were significantly less in stimulated CIA rats compared to unstimulated CIA rats (P < 0.05). Histopathological score of inflammation and cartilage loss in stimulated CIA rats were no different from that of normal (P > 0.05). In conclusion, abdominal VNS alleviates CIA and could be a promising therapy for patients with RA.

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

Transcutaneous vagus nerve stimulation, which involves the application of electrical currents to the cervical (tcVNS) or auricular (taVNS) branches of the vagus nerve, may be a potential treatment for improving cognitive dysfunction. taVNS may improve cognitive performance in healthy adults, and fewer studies have been performed on the effects of tcVNS on cognition in healthy subjects. We conducted a randomized, single-blind, crossover-controlled trial to investigate the effects of tcVNS stimulation on cognitive function and neural activity in the brains of healthy adults. This study provides support for further tcVNS studies for the treatment of cognitive impairment. Twenty-one participants were randomly divided into two groups, A and B. Group A received tcVNS first and then sham-tcVNS, while group B received the intervention in the reverse order, receiving sham stimulation first and then true stimulation. All subjects were required to perform cognitive function tests before and after receiving intervention, and functional magnetic resonance imaging (fMRI) was performed concurrently during the intervention. We hypothesized that tcVNS would have an effect on the cognitive performance of the subjects and alter the neural activity of the brain. The present study showed that tcVNS had beneficial effects on cognitive performance, mainly improving memory and language skills and attention. tcVNS intervention produced significant spontaneous neural activity in the calcarine gyrus, fusiform gyrus, lingual gyrus, and parahippocampal gyrus of the brain. Future tcVNS/fMRI trials will need to explore the effects of changes in stimulus parameters on the neural activity response of the brain.

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

Over 100,000 individuals in the United States lost their lives secondary to drug overdose in 2021, with opioid use disorder (OUD) being a leading cause. Pain is an important component of opioid withdrawal, which can complicate recovery from OUD. This study's objectives were to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS), a technique shown to reduce sympathetic arousal in other populations, on pain during acute opioid withdrawal and to study pain's relationships with objective cardiorespiratory markers. Twenty patients with OUD underwent opioid withdrawal while participating in a two-hour protocol. The protocol involved opioid cues to induce opioid craving and neutral conditions for control purposes. Adhering to a double-blind design, patients were randomly assigned to receive active tcVNS (n = 9) or sham stimulation (n = 11) throughout the protocol. At the beginning and end of the protocol, patients' pain levels were assessed using the numerical rating scale (0-10 scale) for pain (NRS Pain). During the protocol, electrocardiogram and respiratory effort signals were measured, from which heart rate variability (HRV) and respiration pattern variability (RPV) were extracted. Pre- to post- changes (denoted with a Δ) were computed for all measures. Δ NRS Pain scores were lower (P = 0.045) for the active group (mean ± standard deviation: -0.8 ± 2.4) compared to the sham group (0.9 ± 1.0). A positive correlation existed between Δ NRS pain scores and Δ RPV (Spearman's ρ = 0.46; P = 0.04). Following adjustment for device group, a negative correlation existed between Δ HRV and Δ NRS Pain (Spearman's ρ = -0.43; P = 0.04). This randomized, double-blind, sham-controlled pilot study provides the first evidence of tcVNS-induced reductions in pain in patients with OUD experiencing opioid withdrawal. This study also provides the first quantitative evidence of an association between breathing irregularity and pain. The correlations between changes in pain and changes in objective physiological markers add validity to the data. Given the clinical importance of reducing pain non-pharmacologically, the findings support the need for further investigation of tcVNS and wearable cardiorespiratory sensing for pain monitoring and management in patients with OUD.

Vagus Nerve Stimulation Accelerates Thrombosis via α7 Nicotinic Acetylcholine Receptors and Improves Clot Formation in Hemophilia A Mice

INTRODUCTION: Hemophilia A, factor VIII deficiency, decreases thrombin and fibrin formation, resulting in abnormal bleeding. Vagus nerve stimulation (VNS) increases thrombin generation via α7 nicotinic acetylcholine receptors (α7nAChR). We reasoned that VNS would improve local clot stability in a FeCl3-induced thrombosis model in wild-type (WT) and factor VIII–deficient (F8-KO), but not in α7nAChR-deficient (α7-KO) mice. METHODS: Mice underwent left cervical VNS (1 V, 30 Hz, 2 ms, 5 minute), and then FeCl3 solution was applied to the right carotid artery. For WT and α7-KO experiments, a 5% solution was applied for 1 minute. For F8-KO experiments, a 10% solution was applied for 3 minutes. Time to occlusion (TTO) was defined as absence of arterial waveform for greater than 1 minute. RESULTS: In WT mice, VNS significantly decreases TTO (VNS vs sham: 7.1 ± 1.3 vs 15.8 ± 3.4 minutes, n = 5, p < 0.05), but fails to decrease TTO in α7-KO mice (VNS vs sham: 19.3 ± 3.7 vs 17.9 ± 4.3 minutes, n = 5, p = NS). F8-KO mice have significantly longer TTO vs WT mice (WT vs F8-KO sham: 6.55 ± 0.63 minutes vs 25 ± 0 minutes, n = 6, p <0.0001). VNS significantly decreases TTO in F8-KO mice (F8-KO VNS vs F8-KO sham: 9.26 ± 1.38 minutes vs 25 ± 0 minutes, n = 6, p < 0.0001) (Figure).Figure.: F8-KO, factor VIII–deficient; VNS, vagus nerve stimulation.CONCLUSION: VNS improves local clot stability. VNS requires α7nAChR, but bypasses factor VIII deficiency, suggesting that vagal control of thrombin generation is independent of this critical clotting factor.

Corrections to "A Numerical Model of the Acute Cardiac Effects Provoked by Cervical Vagus Nerve Stimulation".

In the above paper [1] there are minor errors in several equations, which we correct here. There is also an error in Fig. 5, which we also correct here.

PO004 / #578 EFFECT OF TRANSCUTANEOUS CERVICAL VAGUS NERVE STIMULATION WITH DIFFERENT PARAMETERS ON THE CARDIAC AUTONOMIC FUNCTION: E-POSTER VIEWING

Studies showed that transcutaneous cervical vagus nerve stimulation (tcVNS) could regulate cardiac autonomic function[1,2]. The handheld device was often used in tcVNS which delivers low-voltage electric signals by 1 millisecond of 5-kHz sine wave series repeated every 40 milliseconds. Recently, our study showed that there was a parameter specificity for auricular vagus nerve stimulation in the regulation of the heart rate variability (HRV)[3]. Therefore, the present study aims to investigate the effect of tcVNS with a new tonic-like parameter, and its difference from the traditional burst-like parameter in the regulation of HRV.

Transcutaneous Cervical Vagus Nerve Stimulation Reduces Respiratory Variability in the Context of Opioid Withdrawal.

Opioid withdrawal's physiological effects are a major impediment to recovery from opioid use disorder (OUD). Prior work has demonstrated that transcutaneous cervical vagus nerve stimulation (tcVNS) can counteract some of opioid withdrawal's physiological effects by reducing heart rate and perceived symptoms. The purpose of this study was to assess the effects of tcVNS on respiratory manifestations of opioid withdrawal - specifically, respiratory timings and their variability. Patients with OUD (N = 21) underwent acute opioid withdrawal over the course of a two-hour protocol. The protocol involved opioid cues to induce opioid craving and neutral conditions for control purposes. Patients were randomly assigned to receive double-blind active tcVNS (n = 10) or sham stimulation (n = 11) throughout the protocol. Respiratory effort and electrocardiogram-derived respiration signals were used to estimate inspiration time (Ti), expiration time (Te), and respiration rate (RR), along with each measure's variability quantified via interquartile range (IQR). Comparing the active and sham groups, active tcVNS significantly reduced IQR(Ti) - a variability measure - compared to sham stimulation (p = .02). Relative to baseline, the active group's median change in IQR(Ti) was 500 ms less than the sham group's median change in IQR(Ti). Notably, IQR(Ti) was found to be positively associated with post-traumatic stress disorder symptoms in prior work. Therefore, a reduction in IQR(Ti) suggests that tcVNS downregulates the respiratory stress response associated with opioid withdrawal. Although further investigations are necessary, these results promisingly suggest that tcVNS - a non-pharmacologic, non-invasive, readily implemented neuromodulation approach - can serve as a novel therapy to mitigate opioid withdrawal symptoms.

Transcutaneous cervical vagus nerve stimulation reduces behavioral and physiological manifestations of withdrawal in patients with opioid use disorder: A double-blind, randomized, sham-controlled pilot study

BackgroundOpioid Use Disorder (OUD) is a serious public health problem, and the behavioral and physiological effects of opioid withdrawal can be a major impediment to recovery. Medication for OUD is currently the mainstay of treatment; however, it has limitations and alternative approaches are needed. ObjectiveThe purpose of this study was to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on behavioral and physiological manifestations of acute opioid withdrawal. MethodsPatients with OUD undergoing acute opioid withdrawal were randomly assigned to receive double blind active tcVNS (N = 10) or sham stimulation (N = 11) while watching neutral and opioid cue videos. Subjective opioid withdrawal, opioid craving, and anxiety were measured using a Visual Analogue Scale (VAS). Distress was measured using the Subjective Units of Distress Scale (SUDS), and pain was measured using the Numerical Rating Scale (NRS) for pain. Electrocardiogram signals were measured to compute heart rate. The primary outcomes of this initial phase of the clinical trial (ClinicalTrials.gov NCT04556552) were heart rate and craving. ResultstcVNS compared to sham resulted in statistically significant reductions in subjective opioid withdrawal (p = .047), pain (p = .045), and distress (p = .004). In addition, tcVNS was associated with lower heart rate compared to sham (p = .026). Craving did not significantly differ between groups (p = .11). ConclusionstcVNS reduces behavioral and physiological manifestations of opioid withdrawal, and should be evaluated in future studies as a possible non-pharmacologic, easily implemented approach for adjunctive OUD treatment.

Neuromodulation devices for heart failure

Autonomic imbalance with a sympathetic dominance is acknowledged to be a critical determinant of the pathophysiology of chronic heart failure with reduced ejection fraction (HFrEF), regardless of the etiology. Consequently, therapeutic interventions directly targeting the cardiac autonomic nervous system, generally referred to as neuromodulation strategies, have gained increasing interest and have been intensively studied at both the pre-clinical level and the clinical level. This review will focus on device-based neuromodulation in the setting of HFrEF. It will first provide some general principles about electrical neuromodulation and discuss specifically the complex issue of dose-response with this therapeutic approach. The paper will thereafter summarize the rationale, the pre-clinical and the clinical data, as well as the future prospectives of the three most studied form of device-based neuromodulation in HFrEF. These include cervical vagal nerve stimulation (cVNS), baroreflex activation therapy (BAT), and spinal cord stimulation (SCS). BAT has been approved by the Food and Drug Administration for use in patients with HfrEF, while the other two approaches are still considered investigational; VNS is currently being investigated in a large phase III Study.

Vagus Nerve Stimulation for Treatment-Resistant Depression: Current Status of This Novel Treatment

Patients with treatment-resistant or difficult-to-treat major depression (TRD/DTD) have limited proven treatment options. Vagus nerve stimulation (VNS), chronic stimulation of the left cervical vagus nerve using an implantable pulse generator, has been demonstrated in numerous clinical trials to effectively treat TRD/DTD. In this review, seminal and ongoing vagus nerve stimulation trials are summarized and compared, and critical clinical findings are discussed. [ Psychiatr Ann. 2022;52(7):272–282.]

Non-invasive cervical vagus nerve stimulation effects on reaction time and valence image anticipation response

BackgroundNorepinephrine (NE) driven noninvasive vagus nerve stimulation (nVNS), which improves attention and reduces reaction time, augments learning. Equally important, endogenous NE mediated arousal is highly dependent on the valence (positive or negative) of the exogenous stimulus. But to date, no study has measured valence specific effects of nVNS on both functional magnetic resonance imaging (fMRI) anticipation task response and reaction time in healthy individuals. Therefore, the aim of this pilot study was to assess whether nVNS vs sham modulates valence cortical anticipation task response and reaction time in a normative sample. MethodsParticipants received right sided transcutaneous cervical nVNS (N = 12) or sham (N = 12) stimulation during a 3T fMRI scan. Subjects first performed a continuous performance task (CPT) and then a cued anticipation task to images of positively and negatively valenced events during fMRI. Reaction times to cues and Blood oxygen level dependent (BOLD) response were examined over phase to identify effects of nVNS/sham over time. ResultsnVNS reduced reaction time for all valenced image anticipation trials. With the fMRI anticipation task, we observed a valence-specific effect; nVNS increased responsivity to images with negative valence and decreased responsivity to images with positive valence, whereas sham showed an inverse valence response. ConclusionsnVNS was linked to reduced reaction time during the anticipation task. In tandem, nVNS consistently enhanced responsivity to negatively valenced images and diminished responsivity to positively valenced images, suggesting specific nVNS driven endogenous neurotransmitter signaling may contribute.

Transcutaneous Cervical Vagus Nerve Stimulation Induces Changes in the Electroencephalogram and Heart Rate Variability of Healthy Dogs, a Pilot Study.

Transcutaneous cervical vagus nerve stimulation (tcVNS) has been used to treat epilepsy in people and dogs. Objective electroencephalographic (EEG) and heart rate variability (HRV) data associated with tcVNS have been reported in people. The question remained whether EEG and electrocardiography (ECG) would detect changes in brain activity and HRV, respectively, after tcVNS in dogs. Simultaneous EEG and Holter recordings, from 6 client-owned healthy dogs were compared for differences pre- and post- tcVNS in frequency band power analysis (EEG) and HRV. The feasibility and tolerance of the patients to the tcVNS were also noted. In a general linear mixed model, the average power per channel per frequency band was found to be significantly different pre- and post-stimulation in the theta (p = 0.02) and alpha bands (p = 0.04). The pooled power spectral analysis detected a significant decrease in the alpha (p < 0.01), theta (p = 0.01) and beta (p = 0.035) frequencies post-stimulation. No significant interaction was observed between dog, attitude, and stimulation in the multivariate model, neither within the same dog nor between individuals. There was a significant increase in the HRV measured by the standard deviation of the inter-beat (SDNN) index (p < 0.01) and a decrease in mean heart rate (p < 0.01) after tcVNS. The tcVNS was found to be well-tolerated. The results of this pilot study suggest that EEG and ECG can detect changes in brain activity and HRV associated with tcVNS in healthy dogs. Larger randomized controlled studies are required to confirm the results of this study and to assess tcVNS potential therapeutic value.

Vagus Nerve Stimulation Improves Mitochondrial Dysfunction in Post–cardiac Arrest Syndrome in the Asphyxial Cardiac Arrest Model in Rats

Cerebral mitochondrial dysfunction during post–cardiac arrest syndrome (PCAS) remains unclear, resulting in a lack of therapeutic options that protect against cerebral ischemia–reperfusion injury. We aimed to assess mitochondrial dysfunction in the hippocampus after cardiac arrest and whether vagus nerve stimulation (VNS) can improve mitochondrial dysfunction and neurological outcomes. In an asphyxial cardiac arrest model, male Sprague–Dawley rats were assigned to the vagus nerve isolation (CA) or VNS (CA + VNS) group. Cardiopulmonary resuscitation was performed 450 s after pulseless electrical activity. After the return of spontaneous circulation (ROSC), left cervical VNS was performed for 3 h in the CA + VNS group. Mitochondrial respiratory function was evaluated using high-resolution respirometry of the hippocampal tissue. The neurologic deficit score (NDS) and overall performance category (OPC) were assessed at 24, 48, and 72 h after resuscitation. The leak respiration and oxidative phosphorylation capacity of complex I (OXPHOS CI) at 6 h after ROSC were significantly higher in the CA + VNS group than in the CA group (p = 0.0308 and 0.0401, respectively). Compared with the trends of NDS and OPC in the CA group, the trends of those in the CA + VNS group were significantly different, thus suggesting a favorable neurological outcome in the CA + VNS group (p = 0.0087 and 0.0064 between times × groups interaction, respectively). VNS ameliorated mitochondrial dysfunction after ROSC and improved neurological outcomes in an asphyxial cardiac arrest rat model.

Non‐invasive, Spatiotemporal Characterization of Muscle Activation Patterns from Vagus Nerve Stimulation in Human Subjects

Background and HypothesisVagus nerve stimulation (VNS) is used for treatment of epilepsy in over 100,000 patients worldwide and is a potential treatment for inflammatory disorders such as rheumatoid arthritis, diabetes, and sepsis. VNS‐evoked compound nerve action potentials (CNAPs) may have applications as a biomarker of VNS treatment efficacy, but transcutaneous measurement of this activity is obscured by laryngeal muscle artifacts during cervical VNS. Our objective is to develop a more precise understanding of muscle activation patterns that could improve recording and analysis protocols for isolating the vagus nerve (VN) CNAP from EMG artifacts. We hypothesize that analyzing multi‐electrode array (MEA) surface recordings overlying the VN will allow us to characterize this muscle artifact.MethodsTwelve patients undergoing VNS therapy for epilepsy were enrolled in a clinical study at Indiana University School of Medicine (IRB #2006075899). The anatomical dimensions of the neck were recorded for seven of the twelve subjects. A custom‐made MEA with a grid of 32 soft foam electrodes was placed on the skin overlying the VN on each side of the neck with the short axis parallel to the sternocleidomastoid muscle and the midpoint at the level of the laryngeal prominence. Surface potentials were recorded for approximately 20 minutes at the patient’s established device settings.ResultsVNS‐evoked potentials were visualized in nine subjects (three subjects were excluded due to insufficient data). Two probable muscle artifacts were identified, defined as non‐propagating features in the mean response to n &gt; 600 pulses of VNS. The first had an onset latency of ~1‐3 ms, and the second had a latency of ~7‐10 ms. Both artifacts appeared primarily in the electrodes overlying the laryngeal muscles. In one subject, propagating activity at an approximate velocity of 70‐110 m/s was visualized between 1‐2 ms latency.ConclusionThe short latency of the first muscle artifact suggests stimulus signal leakage activating the superior laryngeal nerve. The propagating activity visualized in one subject may show the activity of the external branch of the superior laryngeal nerve, which stimulates the cricothyroid muscle to contract, creating the first muscle artifact. The second artifact with longer latency is likely caused by the recurrent laryngeal nerve, which causes contraction of intrinsic laryngeal muscles such as the posterior cricoarytenoids. Previous analyses may have mischaracterized the first muscle artifact as nerve activity [Usami, K., Kawai, K., Sonoo, M., and Saito, N. (2013). Brain Stimul. 6(4), 615‐623]. The use of MEA‐based recordings clarifies our understanding of the VN’s response to VNS, which may lead to better treatment efficacy and the eventual development of personalized VNS therapies for epilepsy and a range of inflammatory disorders.