Cervical Vagus Nerve Stimulation Research Articles

Transcutaneous cervical vagus nerve stimulation enhances second-language vocabulary acquisition while simultaneously mitigating fatigue and promoting focus

Transcutaneous vagus nerve stimulation (tVNS) is a promising technique for enhancing cognitive performance and skill acquisition. Yet, its efficacy for enhancing learning rate and long-term retention in an ecologically valid learning environment has not been demonstrated. We conducted two double-blind sham-controlled experiments examining the efficacy of auricular tVNS (taVNS: Experiment (1) and cervical tVNS (tcVNS: Experiment (2), on a 5 day second-language vocabulary acquisition protocol among highly selected career linguists at the US Department of Defense’s premier language school. tcVNS produced accelerated recall performance during training (Day 2–4), benefits of which were maintained across a 24 h retention interval with no stimulation at the final test. Consistent with prior work, tcVNS also produced fatigue-mitigating and focus-promoting effects as measured by the Air Force Research Laboratory Mood Questionnaire. Based on the current and the previous findings supporting tVNS’ efficacy on performance, training enhancement, and fatigue mitigation, we believe tcVNS to be an effective learning acceleration tool that can be utilized at language-teaching and other institutions focused on intensive training of cognitive skills.

Brainstem neuronal responses to transcutaneous auricular and cervical vagus nerve stimulation in rats.

Transcutaneous auricular vagus nerve stimulation (taVNS) targets subcutaneous axons in the auricular branch of the vagus nerve at the outer ear. Its non-invasive nature makes it a potential treatment for various disorders. taVNS induces neuromodulatory effects within the nucleus of the solitary tract (NTS), and due to its widespread connectivity, the NTS acts as a gateway to elicit neuromodulation in both higher-order brain regions and other brainstem nuclei (e.g. spinal trigeminal nucleus; Sp5). Our objective was to examine stimulation parameters on single-neuron electrophysiological responses in α-chloralose-anaesthetized Sprague-Dawley rats within NTS and Sp5. taVNS was also compared to traditional cervical VNS (cVNS) on single neuronal activation. Specifically, electrophysiological extracellular recordings were evaluated for a range of frequency and intensity parameters (20-250Hz, 0.5-1.0mA). Neurons were classified as positive, negative or non-responders based on increased activity, decreased activity or no response during stimulation, respectively. Frequency-dependent analysis showed that 20 and 100Hz generated the highest proportion of positive responders in NTS and Sp5 with 1.0mA intensities eliciting the greatest magnitude of response. Comparisons between taVNS and cVNS revealed similar parameter-specific activation for caudal NTS neuronal populations; however, individual neurons showed different activation profiles. The latter suggests that cVNS and taVNS send afferent input to NTS via different neuronal pathways. This study demonstrates differential parameter-specific taVNS responses and begins an investigation of the mechanisms responsible for taVNS modulation. Understanding the neuronal pathways responsible for eliciting neuromodulatory effects will enable more tailored taVNS treatments in various clinical disorders. KEY POINTS: Transcutaneous auricular vagus nerve stimulation (taVNS) offers a non-invasive alternative to invasive cervical vagus nerve stimulation (cVNS) by activating vagal afferents in the ear to induce neuromodulation. Our study evaluated taVNS effects on neuronal firing patterns in the nucleus of the solitary tract (NTS) and spinal trigeminal nucleus (Sp5) and found that 20 and 100Hz notably increased neuronal activity during stimulation in both nuclei. Increasing taVNS intensity not only increased the number of neurons responding in Sp5 but also increased the magnitude of response, suggesting a heightened sensitivity to taVNS compared to NTS. Comparisons between cVNS and taVNS revealed similar overall activation but different responses on individual neurons, indicating distinct neural pathways. These results show parameter-specific and nuclei-specific responses to taVNS and confirm that taVNS can elicit responses comparable to cVNS at the neuronal level, but it does so through different neuronal pathways.

Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management. We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason). We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity. This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms. PROSPERO CRD42023391562.

Transcutaneous cervical vagus nerve stimulation improves sensory performance in humans: a randomized controlled crossover pilot study

Accurate senses depend on high-fidelity encoding by sensory receptors and error-free processing in the brain. Progress has been made towards restoring damaged sensory receptors. However, methods for on-demand treatment of impaired central sensory processing are scarce. Prior invasive studies demonstrated that continuous vagus nerve stimulation (VNS) in rodents can activate the locus coeruleus-norepinephrine system to rapidly improve central sensory processing. Here, we investigated whether transcutaneous VNS improves sensory performance in humans. We conducted three sham-controlled experiments, each with 12 neurotypical adults, that measured the effects of transcutaneous VNS on metrics of auditory and visual performance, and heart rate variability (HRV). Continuous stimulation was delivered to cervical (tcVNS) or auricular (taVNS) branches of the vagus nerve while participants performed psychophysics tasks or passively viewed a display. Relative to sham stimulation, tcVNS improved auditory performance by 37% (p = 0.00052) and visual performance by 23% (p = 0.038). Participants with lower performance during sham conditions experienced larger tcVNS-evoked improvements (p = 0.0040). Lastly, tcVNS increased HRV during passive viewing, corroborating vagal engagement. No evidence for an effect of taVNS was observed. These findings validate the effectiveness of tcVNS in humans and position it as a method for on-demand interventions of impairments associated with central sensory processing dysfunction.

Locus coeruleus features are linked to vagus nerve stimulation response in drug-resistant epilepsy.

The locus coeruleus-norepinephrine system is thought to be involved in the clinical effects of vagus nerve stimulation. This system is known to prevent seizure development and induce long-term plastic changes, particularly with the release of norepinephrine in the hippocampus. However, the requisites to become responder to the therapy and the mechanisms of action are still under investigation. Using MRI, we assessed the structural and functional characteristics of the locus coeruleus and microstructural properties of locus coeruleus-hippocampus white matter tracts in patients with drug-resistant epilepsy responding or not to the therapy. Twenty-three drug-resistant epileptic patients with cervical vagus nerve stimulation were recruited for this pilot study, including 13 responders or partial responders and 10 non-responders. A dedicated structural MRI acquisition allowed in vivo localization of the locus coeruleus and computation of its contrast (an accepted marker of LC integrity). Locus coeruleus activity was estimated using functional MRI during an auditory oddball task. Finally, multi-shell diffusion MRI was used to estimate the structural properties of locus coeruleus-hippocampus tracts. These characteristics were compared between responders/partial responders and non-responders and their association with therapy duration was also explored. In patients with a better response to the therapy, trends toward a lower activity and a higher contrast were found in the left medial and right caudal portions of the locus coeruleus, respectively. An increased locus coeruleus contrast, bilaterally over its medial portions, correlated with duration of the treatment. Finally, a higher integrity of locus coeruleus-hippocampus connections was found in patients with a better response to the treatment. These new insights into the neurobiology of vagus nerve stimulation may provide novel markers of the response to the treatment and may reflect neuroplasticity effects occurring in the brain following the implantation.

Effectiveness and possible brain mechanisms of cervical invasive vagus nerve stimulation (iVNS) intervention for avoidant/restrictive food intake disorder: a case report.

We reported a case of cervical invasive vagus nerve stimulation (iVNS) treatment for avoidant/restrictive food intake disorder (ARFID) in a patient with severe anxiety and depression. This patient was even given a critical illness notice during his hospitalization and all treatment efforts were failed. We aimed to verfiy the effectiveness of iVNS in a patient with ARFID. We first attempted to perform cervical iVNS in this case and then observed the changes in clinical scores. We also analyzed the alterations in brain magnetic resonance imaging characteristics before and after iVNS using multi-modal neuroimagings. After 18 days of iVNS (from 1 to 19 July 2023), the patient's clinical symptoms improved significantly and he rapidly gained 5 kg in weight. The brain functional characteristics of this patient tended toward those of the normal group. Functional connectivities of the medial of orbitalis prefrontal cortex returned to the normal range after iVNS. This is a precedent for performing cervical iVNS in an ARFID patient. Brain neural activity can be modulated through iVNS. The observed improvements in clinical scores and positive changes in brain function validated the effectiveness of iVNS. This case study provides evidence that this intervention technique could be used to reduce the burden on more similar ARFID patients.

The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum.

Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3-54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for p < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.

Transcutaneous cervical vagus nerve stimulation improved motor cortex excitability in healthy adults: a randomized, single-blind, self-crossover design study.

To investigate the effect of transcutaneous cervical vagus nerve stimulation (tcVNS) on motor cortex excitability in healthy adults. Twenty eight healthy subjects were assigned to receive real and sham tcVNS for 30 min. The interval between the real and sham conditions was more than 24 h, and the sequence was random. The central and peripheral motor-evoked potential (MEP) of the right first dorsal interosseous (FDI) muscle was measured by transcranial magnetic stimulation (TMS) before and after stimulation. MEP latency, MEP amplitude and rest motor threshold (rMT) were analyzed before and after stimulation. MEP amplitude, MEP latency and rMT had significant interaction effect between time points and conditions (p < 0.05). After real stimulation, the MEP amplitude was significantly increased (p < 0.001). MEP latency (p < 0.001) and rMT (p = 0.006) was decreased than that of baseline. The MEP amplitude on real condition was higher than that of sham stimulation after stimulation (p = 0.027). The latency after the real stimulation was significantly shorter than that after sham stimulation (p = 0.005). No significantly difference was found in rMT after stimulation between real and sham conditions (p > 0.05). tcVNS could improve motor cortex excitability in healthy adults.

In vivo tracing of the ascending vagal projections to the brain with manganese enhanced magnetic resonance imaging.

The vagus nerve, the primary neural pathway mediating brain-body interactions, plays an essential role in transmitting bodily signals to the brain. Despite its significance, our understanding of the detailed organization and functionality of vagal afferent projections remains incomplete. In this study, we utilized manganese-enhanced magnetic resonance imaging (MEMRI) as a non-invasive and in vivo method for tracing vagal nerve projections to the brainstem and assessing their functional dependence on cervical vagus nerve stimulation (VNS). Manganese chloride solution was injected into the nodose ganglion of rats, and T1-weighted MRI scans were performed at both 12 and 24 h after the injection. Our findings reveal that vagal afferent neurons can uptake and transport manganese ions, serving as a surrogate for calcium ions, to the nucleus tractus solitarius (NTS) in the brainstem. In the absence of VNS, we observed significant contrast enhancements of around 19-24% in the NTS ipsilateral to the injection side. Application of VNS for 4 h further promoted nerve activity, leading to greater contrast enhancements of 40-43% in the NTS. These results demonstrate the potential of MEMRI for high-resolution, activity-dependent tracing of vagal afferents, providing a valuable tool for the structural and functional assessment of the vagus nerve and its influence on brain activity.

Transcutaneous vagal nerve stimulation modulates stress-induced plasma ghrelin levels: A double-blind, randomized, sham-controlled trial

BackgroundTranscutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress. MethodsUsing a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period. ResultsThere were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009). LimitationsTiming of ghrelin measurements, and stimulation of only left vagus nerve. ConclusiontcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

Transcutaneous auricular Vagus Nerve Stimulation and Median Nerve Stimulation reduce acute stress in young healthy adults: a single-blind sham-controlled crossover study.

Stress is a major determinant of health and wellbeing. Conventional stress management approaches do not account for the daily-living acute changes in stress that affect quality of life. The combination of physiological monitoring and non-invasive Peripheral Nerve Stimulation (PNS) represents a promising technological approach to quantify stress-induced physiological manifestations and reduce stress during everyday life. This study aimed to evaluate the effectiveness of three well-established transcutaneous PNS modalities in reducing physiological manifestations of stress compared to a sham: auricular and cervical Vagus Nerve Stimulation (taVNS and tcVNS), and Median Nerve Stimulation (tMNS). Using a single-blind sham-controlled crossover study with four visits, we compared the stress mitigation effectiveness of taVNS, tcVNS, and tMNS, quantified through physiological markers derived from five physiological signals peripherally measured on 19 young healthy volunteers. Participants underwent three acute mental and physiological stressors while receiving stimulation. Blinding effectiveness was assessed via subjective survey. taVNS and tMNS relative to sham resulted in significant changes that suggest a reduction in sympathetic outflow following the acute stressors: Left Ventricular Ejection Time Index (LVETI) shortening (tMNS: p = 0.007, taVNS: p = 0.015) and Pre-Ejection Period (PEP)-to-LVET ratio (PEP/LVET) increase (tMNS: p = 0.044, taVNS: p = 0.029). tMNS relative to sham also reduced Pulse Pressure (PP; p = 0.032) and tonic EDA activity (tonicMean; p = 0.025). The nonsignificant blinding survey results suggest these effects were not influenced by placebo. taVNS and tMNS effectively reduced stress-induced sympathetic arousal in wearable-compatible physiological signals, motivating their future use in novel personalized stress therapies to improve quality of life.

Cervical Vagus Nerve Stimulation Disrupts Gastric Slow Wave Activity in Rats.

Cervical vagus nerve stimulation (cVNS) is a promising neuromodulation therapy for treating symptoms of disease in peripheral organs. The rat is a common animal model for studying and trialing new applications of cVNS therapy, but the stomach and its activity in rats is less well characterized than other animals, such as pigs. We sought to investigate the effects of acute, in vivo cVNS on gastric bioelectrical activity as an intermediate step to computational modeling of the effects of cVNS on gastric smooth muscle electromechanical coupling. Here we show a method of detecting bioelectrical gastric slow wave events using a non-linear energy operator. The marked events are compared to the underlying bioelectrical slow wave activity.The mean propagation velocity before stimulation was 0.79 ± 0.31 mm s-1, and the mean interval was 17.4 ± 1.4 s. During cVNS, there was a significant increase in velocity (1.02 ± 0.69 mm s-1; p < 0.001), and decrease in interval (15.4 ± 2.9 s; p = 0.0196). At stimulation onset, premature slow waves were induced at an ectopic pacemaker location and waves originating at the ectopic and initial pacemaker sites continued to collide following the cessation of cVNS.This work forms the basis for more thorough investigation of the effects of cVNS on gastric bioelectrical slow wave activity and consequential smooth muscle contractions in rats. A better understanding of the effects of cVNS on gastric function will allow the refinement of cVNS therapy to target the stomach, and avoid off-target effects on the stomach.Clinical relevance- This work presents a signal processing and analysis approach for the investigation of cervical vagus nerve stimulation on gastric bioelectrical activity in rats. Vagus nerve stimulation may enable the control and amelioration of hunger, gastric emptying, or functional gastric disorders.

Multi-session transcutaneous auricular vagus nerve stimulation for Parkinson's disease: evaluating feasibility, safety, and preliminary efficacy.

In pre-clinical animal models of Parkinson's disease (PD), vagus nerve stimulation (VNS) can rescue motor deficits and protect susceptible neuronal populations. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive alternative to traditional invasive cervical VNS. This is the first report summarizing the safety, feasibility, and preliminary efficacy of repeated sessions of taVNS in participants with PD. To evaluate the feasibility, safety, and possible efficacy of taVNS for motor and non-motor symptoms in mild to moderate PD. This is a double-blind, sham controlled RCT (NCT04157621) of taVNS in 30 subjects with mild to moderate PD without cognitive impairment. Participants received 10, 1-h taVNS sessions (25 Hz, 200% of sensory threshold, 500 μs pulse width, 60 s on and 30 s off) over a 2-week period. Primary outcome measures were feasibility and safety of the intervention; secondary outcomes included the MDS-UPDRS, cognitive function and self-reported symptom improvement. taVNS treatment was feasible, however, daily in-office visits were reported as being burdensome for participants. While five participants in the taVNS group and three in the sham group self-reported one or more minor adverse events, no major adverse events occurred. There were no group differences on blood pressure and heart rate throughout the intervention. There were no group differences in MDS-UPDRS scores or self-reported measures. Although global cognitive scores remained stable across groups, there was a reduction in verbal fluency within the taVNS group. taVNS was safe, and well-tolerated in PD participants. Future studies of taVNS for PD should explore at-home stimulation devices and optimize stimulation parameters to reduce variability and maximize engagement of neural targets.

Effect of transcutaneous cervical vagus nerve stimulation on declarative and working memory in patients with Posttraumatic Stress Disorder (PTSD): A pilot study

BackgroundPosttraumatic stress disorder (PTSD) is associated with changes in multiple neurophysiological systems, including verbal declarative memory deficits. Vagus Nerve Stimulation (VNS) has been shown in preliminary studies to enhance function when paired with cognitive and motor tasks. The purpose of this study was to analyze the effect of transcutaneous cervical VNS (tcVNS) on attention, declarative and working memory in PTSD patients. MethodsFifteen PTSD patients were randomly assigned to active tcVNS (N = 8) or sham (N = 7) stimulation in a double-blinded fashion. Memory assessment tests including paragraph recall and N-back tests were performed to assess declarative and working memory function when paired with active/sham tcVNS once per month in a longitudinal study during which patients self-administered tcVNS/sham twice daily. ResultsActive tcVNS stimulation resulted in a significant improvement in paragraph recall performance following pairing with paragraph encoding for PTSD patients at two months (p < 0.05). It resulted in a 91 % increase in paragraph recall performance within group (p = 0.03), while sham tcVNS exhibited no such trend in performance improvement. In the N-back study, positive deviations in accuracy, precision and recall measures on different day visits (7,34,64,94) of patients with respect to day 1 revealed a pattern of better performance of the active tcVNS population compared to sham VNS which did not reach statistical significance. LimitationsOur sample size was small. ConclusionsThese preliminary results suggest that tcVNS improves attention, declarative and working memory, which may improve quality of life and productivity for patients with PTSD. Future studies are required to confirm these results.

Sympathetic components in left and right human cervical vagus nerve: implications for vagus nerve stimulation.

Cervical vagus nerve stimulation is in a great variety of clinical situations indicated as a form of treatment. It is textbook knowledge that at the cervical level the vagus nerve contains many different fiber classes. Yet, recently, several reports have shown that this nerve also may contain an additional class of potentially noradrenergic fibers, suggested to denote efferent sympathetic fibers. As such, the nature and presence of these fibers should be considered when choosing a stimulation protocol. We have studied human vagus material extracted from dissection room cadavers in order to further confirm the presence of this class of fibers, to study their origin and direction within the nerve and to determine their distribution and variability between subjects and pairs of left and right nerves of the same individual. Sections were studied with immunohistochemical techniques using antibodies against tyrosine hydroxylase (TH: presumed to indicate noradrenergic fibers), myelin basic protein and neurofilament. Our results show that at least part of the TH-positive fibers derive from the superior cervical ganglion or sympathetic trunk, do not follow a cranial but take a peripheral course through the nerve. The portion of TH-positive fibers is highly variable between individuals but also between the left and right pairs of the same individual. TH-positive fibers can distribute and wander throughout the fascicles but maintain a generally clustered appearance. The fraction of TH-positive fibers generally diminishes in the left cervical vagus nerve when moving in a caudal direction but remains more constant in the right nerve. These results may help to determine optimal stimulation parameters for cervical vagus stimulation in clinical settings.

Transcutaneous auricular vagus nerve stimulation would be an alternative to implantable cervical vagus nerve stimulation in some situation.

Implantable cervical vagus nerve stimulation (iVNS) is a representative and promising neuromodulation. However, the invasive nature restricts its application. Traditional auricular acupuncture treatment has a long history. The auricular branch of the vagus nerve (ABVN) is a branch on the surface of the ear. Some studies demonstrates that transcutaneous auricular vagus nerve stimulation (taVNS) would achieve similar effects as iVNS. TaVNS and iVNS share a common anatomical basis and acting mechanism. In this article, we made a comparison between iVNS and taVNS in indications and efficacy. The recent studies have revealed similar clinical efficacy of taVNS, taVNS would expand the indication of iVNS. High-quality clinical evidences are needed before taVNS become be an alternative of iVNS.

Noninvasive vagus nerve stimulation for migraine: a systematic review and meta-analysis of randomized controlled trials.

Medication is commonly used to treat migraine. However, patients may experience adverse events or fail to respond to medication. In recent years, neuromodulation techniques have emerged as potential non-pharmacological therapy for migraine. This article focuses on a systematic review and meta-analysis of randomized controlled trials of non-invasive vagus nerve stimulation (n-VNS) for migraine to determine the efficacy, safety and tolerability of n-VNS. We searched PUBMED, EMBASE, and Cochrane Center Register of Controlled Trials databases up to July 15, 2022. Primary outcomes were monthly reduced migraine/headache days, and pain-free rates within 2 h. Secondary outcomes were ≥ 50% responder rate, headache intensity, monthly acute medication reduction days, and adverse events. Meta-analysis shows that non-invasive cervical vagus nerve stimulation (n-cVNS) significantly impacted ≥50% responder rate (OR, 1.64; 95% CI, 1.1 to 2.47; p = 0.02), but had no significant effect on reducing migraine days (MD, -0.46; 95% CI, -1.21 to 0.29; p = 0.23) and headache days (MD, -0.68; 95% CI, -1.52 to 0.16; p = 0.11). In contrast, low-frequency non-invasive auricular vagus nerve stimulation (n-aVNS) was found to significantly reduce the number of migraine days (MD, -1.8; 95% CI, -3.34 to -0.26; p = 0.02) and headache intensity (SMD, -0.7; 95% CI, -1.23 to -0.17; p = 0.009), but not the number of acute medication days per month (MD, -1.1; 95% CI, -3.84 to 1.64; p = 0.43). In addition, n-cVNS was found safe and well-tolerated in most patients. These findings show that n-VNS is a promising method for migraine management.

Transcutaneous auricular vagus nerve stimulation may elicit anti-inflammatory actions through activation of the hypothalamic-pituitary-adrenal axis in humans

Introduction: Since the discovery of the cholinergic anti-inflammatory pathway, vagus nerve stimulation (VNS) has been suggested as a treatment option for chronic inflammatory conditions. This pathway relies on efferent vagal nerve fibers. Invasive cervical VNS activates afferent and efferent vagal nerve fibers and, thus, has the potential to directly activate the cholinergic anti-inflammatory pathway. In contrast, transcutaneous auricular VNS (taVNS) activates the auricular branch of the vagus nerve that is purely afferent and projects to the nucleus of the solitary tract. Thus, any anti-inflammatory actions of taVNS are unlikely to result from a direct activation of the cholinergic anti-inflammatory pathway. The objective of this study was to investigate alternative mechanisms by which taVNS may elicit anti-inflammatory effects. The hypothesis was tested that taVNS activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in adrenal cortisol secretion that will then modulate circulatory immune cell numbers. Methods: The study was approved by the appropriate authorities (IRB# 0054_2019 and NCT04177264). Study participants were healthy adults (n=19, 6 male, 13 female). On three consecutive days either taVNS (left ear, 10 Hz, 1-2 mA, 300 μs pulse width) or sham-taVNS (stimulator off) was applied for 10 minutes. A blood sample was drawn at the end of the third day. Plasma cortisol was determined by ELISA (K003-H1W, Arbor Assays, MI). Circulating T-helper cells (CD3+, CD4+), cytotoxic T-cells (CD3+, CD8+), B-cells (CD19+), monocytes (CD14+, CD11b+), and natural killer (NK, CD3-, CD56+) cells were counted using flow cytometry. Statistical significance was assumed at P&lt;0.05 and trends are reported for P&lt;0.15 based on unpaired t-tests. Results: Plasma cortisol levels tended to be higher following taVNS (72.5±9.5 ng/mL) compared to sham-taVNS (52.3±3.8 ng/mL, P=0.09). Following taVNS, the relative number of circulatory B cells was lower (0.48±0.11 % vs. 0.82±0.11 %, P&lt;0.05), while the number of circulatory monocytes was higher (2.21±0.32 % vs 1.58±0.16 %, P=0.06) compared to sham-taVNS. T-helper cells, cytotoxic T cells, and NK cells were not significantly affected by taVNS. In conclusion, the higher plasma cortisol levels following taVNS together with the higher number of circulatory monocytes and lower number of B cells suggest that taVNS elicits anti-inflammatory actions through activation of the HPA axis, because it is known that cortisol increases circulatory monocytes and reduces B cells. The decrease in B cells following taVNS gives rise to the intriguing hypothesis that taVNS may prevent secondary treatment failure to biologic drugs in chronic inflammatory conditions by reducing production of anti-drug antibodies. Funding: This study was supported by a grant from the American Osteopathic Association (Grant No.: 19137759). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Transcutaneous Cervical Vagus Nerve Stimulation Enhances Second-Language Vocabulary Acquisition While Simultaneously Mitigating Fatigue and Promoting Focus (P2-12.002)

<h3>Objective:</h3> To examine whether transcutaneous cervical and auricular vagus nerve stimulation (tcVNS &amp; taVNS) could enhance second language vocabulary acquisition among career linguists in a realistic multi-day learning protocol. <h3>Background:</h3> Cognitive performance and skill proficiency are important in a wide variety of careers. Recently, transcutaneous vagus nerve stimulation (tVNS) has emerged as a promising technique to enhance learning and skill acquisition. tVNS efficacy in a realistic, multi-day learning protocol has not been demonstrated. <h3>Design/Methods:</h3> We conducted two double-blind controlled experiments examining the efficacy of tcVNS and taVNS on a 5-day second-language vocabulary acquisition protocol in career linguists at the US Defense Language Institute Foreign Language Center. <h3>Results:</h3> tcVNS produced statistically significant benefit during training (Day 2–4; model estimated mean performance: sham-37.5% vs ctVNS-46%, <i>p</i> = .025), and the training benefit was sustained on the final test conducted at a 24-hour delay where no stimulation was administered. Additionally, using pre- and post-training day mood rating as measured by Air Force Research Laboratory Mood Questionnaire, tcVNS promoted focus (<i>p</i> = .001) and mitigated fatigue (<i>p</i> = .036). <h3>Conclusions:</h3> Our findings suggest that tcVNS promotes learning by inducing neuroplasticity as well as enhancing focus and mitigating fatigue. tcVNS training benefits are sustained for at least 24 hours after stimulation. Based on current and related demonstration of training enhancement, we believe tcVNS could be beneficial in language learning as well as acquisition of skills in intensive learning environments. This research was developed with funding from the Defense Advanced Research Projects Agency (DARPA). The views, opinions and/or findings expressed are those of the author and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. <b>Disclosure:</b> Dr. Miyatsu has nothing to disclose. Miss Oviedo has nothing to disclose. Miss Reynaga has nothing to disclose. Ms. Karuzis has nothing to disclose. Dr. Martinez has nothing to disclose. Dr. Key has received personal compensation for serving as an employee of Infoscitex. Mrs. McIntire has nothing to disclose. Dr. Aue has received personal compensation for serving as an employee of United States Department of Defense. An immediate family member of Dr. Aue has received personal compensation for serving as an employee of Anthem. Dr. Pirolli has nothing to disclose. Dr. O’Rourke has nothing to disclose. The institution of Dr. McKinley has received research support from AFRL. The institution of Dr. McKinley has received research support from DARPA. Dr. McKinley has received personal compensation in the range of $100,000-$499,999 for serving as a Employee with Air Force Research Laboratory. Dr. Broderick has received personal compensation for serving as an employee of IHMC. Dr. Broderick has received personal compensation for serving as an employee of Wright State Boonshoft School of Medicine. The institution of Dr. Broderick has received research support from United States Department of Defense.

Fractal Microelectrodes for More Energy-Efficient Cervical Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) has the potential to treat various peripheral dysfunctions, but the traditional cuff electrodes for VNS are susceptible to off-target effects. Microelectrodes may enable highly selective VNS that can mitigate off-target effects, but they suffer from the increased impedance. Recent studies on microelectrodes with non-Euclidean geometries have reported higher energy efficiency in neural stimulation applications. These previous studies use electrodes with mm/cm-scale dimensions, mostly targeted for myelinated fibers. This study evaluates fractal microelectrodes for VNS in a rodent model (N = 3). A thin-film device with fractal and circle microelectrodes is fabricated to compare their neural stimulation performance on the same radial coordinate of the nerve. The results show that fractal microelectrodes can activate C-fibers with up to 52% less energy (p = 0.012) compared to circle microelectrodes. To the best of the knowledge, this work is the first to demonstrate a geometric advantage of fractal microelectrodes for VNS in vivo.