Vagal Stimulation Research Articles

Efficacy observation of combined transcutaneous vagus nerve stimulation and transcranial direct current stimulation on gait in 169 subacute stroke patients

Objective: To investigate the combined effect of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation on improving lower limb function in stroke patients. Design: Randomized controlled trial. Subjects/Patients: Subacute stroke patients. Methods: 169 post-stroke hemiplegia patients were randomly divided into 4 groups (control, transcranial direct current stimulation, transcutaneous auricular vagus nerve stimulation, and transcutaneous auricular vagus nerve stimulation combined with transcranial direct current stimulation) and evaluated using the Fugl-Meyer Assessment-Lower Extremity (FMA-LL), Timed Up-and-Go (TUG) test, Modified Barthel Index (MBI), Berg Balance Scale (BBS), gait parameters, and surface electromyography (sEMG). Results: Significant improvements in FMA-LL, MBI, BBS, TUG, gait parameters, and sEMG were noted in the intervention groups compared with the control, with the transcutaneous auricular vagus nerve stimulation combined with transcranial direct current stimulation group showing the most pronounced improvements. Differences in some outcomes were also notable between the transcutaneous auricular vagus nerve stimulation and transcranial direct current stimulation groups. Conclusion: The combination of transcutaneous auricular vagus nerve stimulation and transcranial direct current stimulation effectively enhances gait, balance, and daily living activities in subacute stroke patients. These benefits are likely due to transcutaneous auricular vagus nerve stimulation activating the solitary and trigeminal nuclei and transcranial direct current stimulation stimulating the motor cortex. Wearable gait analysis systems and electromyography are valuable in clinical gait assessment for these patients.

Transcutaneous auricular vagal nerve stimulation modulates blood glucose in ZDF rats via intestinal melatonin receptors and melatonin secretion

BackgroundMelatonin (MLT) and its receptor deficiency have been shown to be associated with type 2 diabetes mellitus (T2DM). Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive alternative intervention for patients suffering from hyperglycemia. Here, we aimed to investigate the role of taVNS on blood glucose modulation via intestinal melatonin receptors (MRs) and MLT secretion in hyperglycemia.MethodsAdult male Zucker diabetes fatty (ZDF) rats and Zucker lean (ZL) littermates were used. Forty ZDF rats were randomized into ZDF, taVNS, Px + taVNS and Lu + Px + taVNS groups (Px: pinealectomy, Lu: Luzindole). ZL rats served as a control group for comparison with ZDF rats without involvement in the taVNS intervention. Thirty min-taVNS interventions (2/15 Hz, 2 mA, 30 min/days) were administered once daily under anesthesia for 3 consecutive weeks in taVNS, Px + taVNS and Lu + Px + taVNS groups. Body weight and fasting blood glucose (FBG) were measured weekly in all rats, and real-time blood glucose was tested in the ZL and ZDF groups before, during and after the taVNS intervention. Plasma MLT concentration and the expression of MRs in the duodenum, jejunum and ileum were measured by the end of experiments.ResultsCompared with the ZL group, the level of FBG and body weight increased (all p < 0.01), plasma MLT secretion and the expression of MRs in duodenum, jejunum and ileum of ZDF rats decreased obviously (all p < 0.05), respectively. TaVNS can significantly reverse the hyperglycemia by regulating the non-pineal-derived MLT and MRs system in Px + taVNS group. Compared with the ZDF group, the expression of different intestinal MRs in the taVNS group was increased and more compactly arranged (both p < 0.05), the level of plasma MLT secretion was up-regulated (p < 0.01), and FBG and body weight were decreased (both p < 0.01). Meanwhile, after taVNS intervention in rats in the Px + taVNS group, we observed an increase in MLT secretion and the number of intestinal MRs compared with the taVNS group (all p > 0.05). In contrast, ZDF rats in which the pineal gland was excised by taVNS intervention and injected with the MRs antagonist Luzindole did not show these changes.ConclusionThe glucose reduction effect of taVNS may be related to regulating MLT levels and expressing intestinal MRs.

An update on the pharmacotherapy of postpartum depression.

Extensive research has been conducted on postpartum depression (PPD) over the past century, and yet no definitive answer regarding its etiopathogenesis, risk factors, genetic predilection, and treatment has been found. The few preclinical and clinical studies propose that maternal brain adaptations to the endocrinological, immunological, and behavioral changes and external sociodemographic risk factors in the perinatal period make women more vulnerable to anxiety and depression. Irrespective of the cause, a dilemma exists regarding the type of help to provide postpartum mothers. With very few treatment options at our disposal, deciding between psychotherapy, pharmacological, and non-pharmacological therapy on a case-by-case basis is unproductive because in developing countries infrastructure is limited and the availability of medications, especially for psychiatric illnesses, is still evolving. Hence, regardless of psychotherapy, antidepressants remain the first line of treatment with selective serotonin reuptake inhibitors (SSRIs); sertraline has the best efficacy and safety profile in breastfeeding women. As endocrine factors play a significant role in etiopathogenesis, hormonal therapy with oxytocin has been shown to be efficacious, and studies investigating the role of testosterone in treating PPD are also under way. In 2019, the US Food and Drug Administration (FDA) approved the first and only drug for the sole purpose of treating PPD, brexanolone. Zuranolone, a drug recently approved by the FDA, has a similar mechanism of action to brexanolone. For breastfeeding mothers reluctant to use pharmacotherapy, somatic therapy has been studied, including bright light therapy, vagal nerve stimulation, and newer noninvasive interventions. This article encompasses a short note on PPD, including its etiopathogenesis and clinical characteristics, and recapitulates the various available and evolving pharmacological and nonpharmacological therapies.

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

Abstract Background We reported a case of cervical invasive vagus nerve stimulation (iVNS) treatment for avoidant/restrictive food intake disorder (ARFID) patient with severe anxiety and depression. This patient was even given a critical illness notice during his hospitalization and all treatment efforts were failed. Methods 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. Results After 18 days of iVNS (from July 1, 2023 to July 19, 2023), the patient's clinical symptoms improved significantly and he rapidly gained 5kg 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. Conclusions 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.

Current and Novel Therapies for Cluster Headache: A Narrative Review.

Cluster headache (CH) is an excruciating and debilitating primary headache disorder. The prevalence is up to 1.3%, and the typical onset is around age 30. Often misdiagnosed as migraine, particularly in children, the diagnosis rate of CH has been increasing among women. CH is characterized by intense unilateral pain and autonomic symptoms, significantly impacting patients' quality of life, mental health, and productivity.Genetic associations suggest a familial risk for developing CH, with lifestyle factors also potentially playing a role. The pathophysiology involves alterations in both central and peripheral nervous system, with the hypothalamus, trigeminocervical complex, and neuropeptides such as calcitonin gene-related peptide (CGRP) being implicated.Nonpharmacological treatments focus on patient education and lifestyle modifications, while pharmacological treatments include acute therapies such as oxygen and subcutaneous or nasal sumatriptan, as well as preventive therapies like verapamil, lithium, and CGRP monoclonal antibodies. Transitional options include oral corticosteroids and greater occipital nerve injections. Emerging interventional procedures offer new avenues for managing refractory cases. Noninvasive vagal nerve stimulation and occipital nerve stimulation show promise for both acute and preventive treatment. Careful consideration of safety profiles is crucial in specific populations such as pregnant patients and children.Current treatments still leave patients highly burdened by limited efficacy and side effects. Future research continues to explore novel pharmacological targets, interventional procedures, and the potential role of psychedelics in CH management. Comprehensive, multifaceted treatment strategies are essential to improve the daily functioning and quality of life for individuals with CH.

Transcutaneous Auricular Vagus Nerve Stimulation for Visually Induced Motion Sickness: An eLORETA Study

Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive form of electrical brain stimulation, has shown potent therapeutic potential for a wide spectrum of conditions. How taVNS influences the characterization of motion sickness – a long mysterious syndrome with a polysymptomatic onset – remains unclear. Here, to examine taVNS-induced effects on brain function in response to motion-induced nausea, 64-channel electroencephalography (EEG) recordings from 42 healthy participants were analyzed; collected during nauseogenic visual stimulation concurrent with taVNS administration, in a crossover randomized sham-controlled study. Cortical neuronal generators were estimated from the obtained EEG using exact low-resolution brain electromagnetic tomography (eLORETA). While both sham and taVNS increased insula activation during electrical stimulation, compared to baseline, taVNS additionally augmented middle frontal gyrus neuronal activity. Following taVNS, brain regions including the supramarginal, parahippocampal, and precentral gyri were activated. Contrasting sham, taVNS markedly increased activity in the middle occipital gyrus during stimulation. A repeated-measures ANOVA showed that taVNS reduced motion sickness symptoms. This reduction in symptoms correlated with taVNS-induced neural activation. Our findings provide new insights into taVNS-induced brain changes, during and after nauseogenic stimuli exposure, including accompanying behavioral response. Together, these findings suggest that taVNS has promise as an effective neurostimulation tool for motion sickness management.

Vagus Nerve Stimulation for Neurologic Recovery

Neural plasticity, a potential mode of managing various neurologic diseases, can be modulated via bursts of neurotransmitter release, including norepinephrine and acetylcholine. One method to do so is by electrically stimulating the vagus nerve while performing a specific task. Vagus nerve stimulation (VNS) has proven to be a viable intervention for conditions, including treatment-resistant epilepsy, depression, and, more recently, motor recovery after ischemic stroke. This article aims to explain the neurobiologic mechanism of VNS-induced cortical plasticity. It highlights both animal and human studies of VNS therapy, with a primary focus on recovery after stroke, traumatic brain injury, and spinal cord injury recovery. Furthermore, we discuss the long-term effects of VNS therapy, suggest potential solutions to overcome challenges encountered in previous studies, and elaborate on future directions in the field.

The effect of Vagus nerve stimulation (VNS) on seizure control, cognitive function, and quality of life in individuals with drug-resistant epilepsy: A systematic review article.

To evaluate the effect of vagus nerve stimulation (VNS) on seizure control, cognitive functions, and quality of life in individuals with drug-resistant epilepsy. An extensive search of electronic databases was carried out in order to carry out this systematic review. The databases Google Scholar, Embase, PubMed, and the Cochrane Library were searched first to carryout gray literature. To reduce the quantity of pointless studies in the advanced search, the search is limited to "human studies" and "English language" publications only. Combining keywords and Medical Subject Headings (MeSH) terms like ("Vagus Nerve Stimulation" OR "VNS") AND ("Epilepsy" OR "Seizure Control") AND ("Cognitive Function" OR "Quality of Life"). Studies that have been published up to November 30/2023 were included. The search strategy yielded a total of 392 relevant studies. The mean age of participant's ranges from 11 years to 33 years. The duration of follow-up ranging from 6 to 36 months. Eleven studies were included in the review. The mean≥50% response rate after VNS therapy was 56.94% ranged from 48.90% to 83.00%. Four and three studies provided information about Quality of Life in Epilepsy Inventory (QOLIE-31) and The Liverpool Seizure Severity Scale (LSSS) questionnaires respectively. Epilepsy is a chronic disease characterized by sudden abnormal discharge of brain neurons, which leads to transient brain dysfunction and the presence of spontaneous recurrent seizures. Vagus nerve stimulation has recently been proposed as a potential tool in the treatment of seizure, depressive symptoms, and cognitive impairments. There has been variation in the effects of VNS treatment on seizure control, cognitive functions, and quality of life among patients with drug-resistant epilepsy. So, a comprehensive review of exciting literature is important to see the pooled effect. Previous systematic review and meta-analysis papers were mostly randomized control trial type with specific diseases. The use of a wider variety of study designs than only randomized controlled trials is important. So, we included retrospective and prospective cohort studies in addition to randomized control trials. This enables a more thorough assessment of the connection between quality of life, cognitive function, and vagus nerve stimulation. In addition, the paper looks at a wide range of disease kinds and patterns. We have established a uniform and comprehensive approach throughout the selected studies by mandating the inclusion of all three crucial parameters: vagus nerve stimulation, cognitive function, and quality of life. This systematic review examined 392 relevant studies on vagus nerve stimulation (VNS) therapy, with participants ranging from 11 to 33 years old and follow-up durations of 6-36 months. Eleven studies were included, and the mean response rate after VNS therapy was 56.94%, ranging from 48.90% to 83.00%. The review also reported on quality of life and cognitive function, and seizure severity frequency result from several studies.

First-in-human microelectrode recordings from the vagus nerve during clinical vagus nerve stimulation.

Vagus nerve stimulation (VNS) is an effective treatment for people with drug-resistant epilepsy. However, its mechanisms of action are poorly understood, including which nerve fibers are activated in humans during VNS in typical clinical settings and which are required for clinical efficacy. In particular, there have been no intraneural recordings of vagus nerve fiber activation in awake humans undergoing chronic VNS. In this study, for the first time, we report recordings from the vagus nerve in this setting. The recordings were performed using a sterile tungsten microelectrode inserted percutaneously into the cervical vagus nerve under ultrasound guidance. The clinical VNS systems were used to deliver stimulation while activity in the vagus nerve was recorded. In addition to activating myelinated axons at low currents, we provide evidence that VNS can also activate unmyelinated C fibers in the vagus nerve at currents <1 mA. These results add to our understanding of how VNS exerts its beneficial effects in drug-resistant epilepsy. Here we describe for the first time, electrical recordings from the vagus nerve in awake drug-resistant epilepsy patients with an implanted vagus nerve stimulation (VNS) device. We found that the VNS device was able to activate both myelinated and unmyelinated fibers within the vagus nerve, whichcontributes to our understanding of how VNS works in the context of drug-resistant epilepsy.

Magnetic vagus nerve stimulation ameliorates contrast-induced acute kidney injury by circulating plasma exosomal miR-365-3p

BackgroundContrast-induced acute kidney injury (CI-AKI) is manifested by a rapid decline in renal function occurring within 48–72 h in patients exposed to iodinated contrast media (CM). Although intravenous hydration is currently the effective method confirmed to prevent CI-AKI, it has several drawbacks. Some investigations have demonstrated the nephroprotective effects of vagus nerve stimulation (VNS) against kidney ischemia-reperfusion injury, but no direct research has investigated the use of VNS for treating CI-AKI. Additionally, most current VNS treatment applies invasive electrical stimulator implantation, which is largely limited by the complications. Our recent publications introduce the magnetic vagus nerve stimulation (mVNS) system pioneered and successfully used for the treatment of myocardial infarction. However, it remains uncertain whether mVNS can mitigate CI-AKI and its specific underlying mechanisms. Therefore, we herein evaluate the potential therapeutic effects of mVNS on CM-induced nephropathy in rats and explore the underlying mechanisms.ResultsmVNS treatment was found to significantly improve the damaged renal function, including the reduction of elevated serum creatinine (Scr), blood urea nitrogen (BUN), and urinary N-acetyl-β-D-glucosaminidase (NAG) with increased urine output. Pathologically, mVNS treatment alleviated the renal tissue structure injury, and suppressed kidney injury molecule-1 (KIM-1) expression and apoptosis in renal tubular epithelial cells. Mechanistically, increased circulating plasma exosomal miR-365-3p after mVNS treatment enhanced the autophagy and reduced CM-induced apoptosis in renal tubular epithelial cells by targeting Ras homolog enriched in brain (Rheb).ConclusionsIn summary, we demonstrated that mVNS can improve CI-AKI through enhanced autophagy and apoptosis inhibition, which depended on plasma exosomal miR-365-3p. Our findings highlight the therapeutic potential of mVNS for CI-AKI in clinical practice. However, further research is needed to determine the optimal stimulation parameters to achieve the best therapeutic effects.Graphical abstract

Importance of the left superior ganglionated plexus ablation for the denervation of atrioventricular node: the impact of patient gender and bradycardia phenotype

Abstract Background Cardioneuroablation has been proposed as a new therapeutic option in selected patients with symptomatic functional bradyarrhythmia including recurrent neurally-mediated syncope. The contribution of individual ganglionated plexi to cardiac autonomic regulations is not fully established. Purpose It appears that ablation of the left superior ganglionated plexus (LSGP) is inoperable for the denervation of the sinoatrial node (SAN) and infrequently required for the denervation of the atrioventricular node (AVN). We explored the conditions that are associated with the need for LSGP ablation. Methods The study included 177 otherwise healthy patients aged 41 ± 12 years; 55% of males; 36% with predominant AVN disorder (29% in males, 44% in females, P &amp;lt;0.05) who underwent their first cardioneuroablation for symptomatic bradyarrhythmias at our centre between 2019 – 2024. Anatomically-navigated radiofrequency ablation with a bi-atrial approach was performed. In all patients, we ablated first the superior paraseptal (former right superior) ganglionated plexus (SPSGP) and inferior paraseptal (former posteromedial left) ganglionated plexus (IPSGP). Extracardiac vagus nerve stimulation (ECVS) via right and left jugular vein in general anaesthesia was used to assess the residual parasympathetic modulation of the AVN. If AVN was not completely denervated after the SPSGP and IPSGP ablation, the LSGP was targeted. Results Ablation of SPSGP and IPSGP resulted in SAN and AVN denervation in the majority of patients. LSGP ablation was required in 39 / 177 (22%) patients; in 31% of females vs. 14% of males (P &amp;lt;0.01); in 41% vs. 12% (P &amp;lt;0.0001) of patients with predominant AVN vs. SAN disorder, respectively. The corresponding decomposition is provided in the Table. In multivariate analysis, both female gender (P &amp;lt;0.05) and AVN disorder (P &amp;lt;0.001) were independently associated with the need for LSGP ablation. When the population was dichotomized into early (September 2019 – December 2021) and recent period (January 2022 – February 2024), the need for LSGP ablation had a downward trend (28% vs. 16%, P &amp;lt;0.05). Conclusions LSGP ablation to finalize the AVN denervation is required in a minority of patients. This need is independently associated with the female gender and predominant AVN disorder. The ECVS guidance in the ablation of SPSGP and IPSGP contributes to the decreasing trend of LSGP ablation, i.e. minimizing the final lesion set.Rate of LSGP ablation

Transcutaneous auricular vagus nerve stimulation mitigates gouty inflammation by reducing neutrophil infiltration in BALB/c mice

Gouty inflammation, caused by uric acid crystal deposition, primarily affects tissues around the toe joints and triggers potent inflammatory responses. Current treatments focus on alleviating inflammation and pain using pharmaceutical agents, which can lead to side effects and complications. This has generated interest in non-pharmacological interventions, such as non-invasive vagus nerve stimulation (VNS). In this study, we explored the anti-inflammatory mechanisms of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of acute gout. Gouty inflammation was induced by injecting monosodium urate (MSU) crystals into the ankle joints of BALB/c mice. The effects of taVNS on the expression of inflammatory cytokines and chemokines in the ankle joint tissue were assessed using real-time quantitative PCR (qPCR), western blotting, histological assessments (H&E staining), and immunohistochemistry (IHC). The role of α7 nicotinic acetylcholine receptors (α7nAChR) was also evaluated by signal blocking. Our findings revealed that MSU significantly elevated gout-associated inflammatory cascades and mediators in the ankle joint. Notably, taVNS at 200 µA and 25 Hz effectively reduced these inflammatory responses, decreasing neutrophil infiltration and chemoattraction within the tissue. taVNS showed significant anti-inflammatory properties by suppressing neutrophil activity, offering a novel therapeutic approach for gout beyond conventional pharmacological methods. Additionally, taVNS holds potential for managing various chronic joint diseases. These results highlight taVNS as a promising non-pharmacological therapy for chronic inflammation.

Autonomic control of the pulmonary circulation: Implications for pulmonary hypertension.

The autonomic regulation of the pulmonary vasculature has been under-appreciated despite the presence of sympathetic and parasympathetic neural innervation and adrenergic and cholinergic receptors on pulmonary vessels. Recent clinical trials targeting this innervation have demonstrated promising effects in pulmonary hypertension, and in this context of reignited interest, we review autonomic pulmonary vascular regulation, its integration with other pulmonary vascular regulatory mechanisms, systemic homeostatic reflexes and their clinical relevance in pulmonary hypertension. The sympathetic and parasympathetic nervous systems can affect pulmonary vascular tone and pulmonary vascular stiffness. Local afferents in the pulmonary vasculature are activated by elevations in pressure and distension and lead to distinct pulmonary baroreflex responses, including pulmonary vasoconstriction, increased sympathetic outflow, systemic vasoconstriction and increased respiratory drive. Autonomic pulmonary vascular control interacts with, and potentially makes a functional contribution to, systemic homeostatic reflexes, such as the arterial baroreflex. New experimental therapeutic applications, including pulmonary artery denervation, pharmacological cholinergic potentiation, vagal nerve stimulation and carotid baroreflex stimulation, have shown some promise in the treatment of pulmonary hypertension.

Vagus nerve stimulation in Parkinson’s disease: a scoping review of animal studies and human subjects research

Parkinson’s Disease (PD) is a prevalent, progressive neurodegenerative disease with motor and non-motor symptoms. Vagus Nerve Stimulation (VNS) has emerged as a potential therapeutic approach for PD, but published research on this topic varies widely. This scoping review maps existing literature on VNS for PD, highlighting stimulation methods, operational parameters, safety profiles, neurophysiological mechanisms, and clinical outcomes in human and animal models. Online databases were used to identify 788 papers published between 2013 and 2023, from which 17 publications on invasive and non-invasive VNS in PD were selected. Studies showed high variability in VNS parameters and study design. Evidence in animal models and human subjects suggests potential neurophysiological effects on PD-related pathology and motor function improvements. However, significant gaps in the literature remain. Future research should include rigorous reporting of study design, standardization of stimulation parameters, and larger sample sizes to ultimately facilitate translation of VNS into clinical practice.

Possible Glycemic Effects of Vagus Nerve Stimulation Evaluated by Continuous Glucose Monitoring in People with Diabetes and Autonomic Neuropathy: A Randomized, Sham-Controlled Trial.

Objective: Autonomic neuropathy is associated with dysglycemia that is difficult to control. We investigated if transcutaneous vagus nerve stimulation (tVNS) could improve glycemic levels. Methods: We randomized 145 individuals with type 1 diabetes (T1D) (n = 70) or type 2 diabetes (T2D) (n = 75) and diabetic autonomic neuropathy (DAN) to self-administered treatment with active cervical tVNS (n = 68) or sham (n = 77) for 1 week (4 daily stimulations) and 8 weeks (2 daily stimulations), separated by a wash-out period of at least 2 weeks. Continuous glucose monitoring (CGM) indices were measured for 104 participants starting 5 days prior to intervention periods, during the 1-week period, and at end of the 8-week period. Primary outcomes were between-group differences in changes in coefficient of variation (CV) and in time in range (TIR 3.9-10 mmol/L). Secondary outcomes were other metrics of CGM and HbA1c. Results: For the 1-week period, median [interquartile range] changes of CV from baseline to follow-up were -1.1 [-4.3;2.0] % in active and -1.5 [-4.4;2.5] % in sham, with no significance between groups (P = 0.54). For TIR, the corresponding changes were 2.4 [-2.1;7.4] % in active and 5.1 [-2.6;8.8] in sham group (P = 0.84). For the 8-week treatment period, changes in CV and TIR between groups were also nonsignificant. However, in the subgroup analysis, persons with T1D receiving active tVNS for 8 weeks had a significant reduction in CV compared with the T1D group receiving sham stimulation (estimated treatment effect: -11.6 [95% confidence interval -20.2;-2.0] %, P = 0.009). None of the changes in secondary outcomes between treatment groups were significantly different. Conclusions: Overall, no significant changes were observed in CGM metrics between treatment arms, while individuals with T1D and DAN decreased their CV after 8 weeks of tVNS treatment.

Immediate modulatory effects of transcutaneous vagus nerve stimulation on patients with Parkinson's disease: a crossover self-controlled fMRI study.

Previous studies have evaluated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of Parkinson's disease (PD). However, the mechanism underlying the effect of taVNS on PD remains to be elucidated. This study aimed to investigate the immediate effects of taVNS in PD patients. This crossover self-controlled study included 50 PD patients. Each patient underwent three sessions of resting-state functional magnetic resonance imaging (rs-fMRI) under three conditions: real taVNS, sham taVNS, and no taVNS intervention. We analyzed whole-brain amplitude of low-frequency fluctuations (ALFF) from preprocessed fMRI data across different intervention conditions. ALFF values in altered brain regions were correlated with clinical symptoms in PD patients. Forty-seven participants completed the study and were included in the final analysis. Real taVNS was associated with a widespread decrease in ALFF in the right hemisphere, including the superior parietal lobule, precentral gyrus, postcentral gyrus, middle occipital gyrus, and cuneus (voxel p < 0.001, GRF corrected). The ALFF value in the right superior parietal lobule during real taVNS was negatively correlated with the Unified Parkinson's Disease Rating Scale Part III (r = -0.417, p = 0.004, Bonferroni corrected). TaVNS could immediately modulate the functional activity of brain regions involved in superior parietal lobule, precentral gyrus, postcentral gyrus, middle occipital gyrus, and cuneus. These findings offer preliminary insights into the mechanism of taVNS in treating PD and bolster confidence in its long-term therapeutic potential. TaVNS appears to reduce ALFF values in specific brain regions, suggesting a potential modulation mechanism for treating PD.

Effects of vagal nerve stimulation parameters on heart rate variability in epilepsy patients.

Vagal nerve stimulation (VNS) is used as an alternative treatment in drug-resistant epilepsy patients. Effects of VNS on the cardiac autonomic system are controversial. In this study, we aimed to investigate the relationship between VNS parameters and heart rate variability (HRV) in epilepsy patients who underwent VNS treatment. Our study included 31 patients who underwent VNS for drug-resistant epilepsy. Patients were divided into groups according to response to VNS and VNS parameters. All patients underwent 24-h Holter ECG. The mean age of 31 VNS-treated epilepsy patients included in the study was 33.87 ± 7.6 years. When patients were grouped according to VNS response, 25 patients were in the VNS responder group and six patients were in the VNS-nonresponder group. When comparing Holter parameters in the VNS responder and non-responder groups, the median HF was significantly lower in the VNS responder group. VNS duration and signal frequency had a positive effect on LF/HF, while output and off time had a negative effect on LF/HF. When ROC analysis was performed to determine the cut-off values of the parameters for the VNS-responsive state, the AUC value of the HF parameter was 0.780, which was statistically significant. The cut-off value to distinguish response to VNS was 156.9. In conclusion, the effects of VNS parameters on HRV parameters are quite complex. However, the conclusion is that VNS is a neuromodulation method that affects the autonomic system in a complex way. Different levels of VNS parameters may also contribute to this effect. Furthermore, HRV parameters can be used as biomarkers to predict the patient population that may benefit from VNS.

Acute transcutaneous auricular vagus nerve stimulation modulates presynaptic SV2A density in healthy rat brain: An invivo microPET study.

Vagus nerve stimulation (VNS) is the subject of exploration as an adjunct treatment for neurological disorders such as epilepsy, chronic migraine, pain, and depression. A non-invasive form of VNS is transcutaneous auricular VNS (taVNS). Combining animal models and positron emission tomography (PET) may lead to a better understanding of the elusive mechanisms of taVNS. We evaluated the acute effect of electrical stimulation of the left vagus nerve via the ear on brain synaptic vesicle glycoprotein 2A (SV2A) as a measure of presynaptic density and glucose metabolism in naïve rats. Female Sprague-Dawley rats were imaged with [11C]UCB-J (n = 11) or [18F]fluorodeoxyglucose ([18F]FDG) PET (n = 13) on two separate days, (1) at baseline, and (2) after acute unilateral left taVNS or sham stimulation (30 min). We calculated the regional volume of distribution (VT) for [11C]UCB-J and standard uptake values (SUV) for [18F]FDG. We observed regional reductions of [11C]UCB-J binding in response to taVNS ranging from 36% to 59%. The changes in taVNS compared to baseline were significantly larger than those induced by sham stimulation. The differences were observed bilaterally in the frontal cortex, striatum, and midbrain. The [18F]FDG PET uptake remained unchanged following acute taVNS or sham stimulation compared to baseline values. This proof-of-concept study shows for the first time that acute taVNS for 30 min can modulate invivo synaptic SV2A density in cortical and subcortical regions of healthy rats. Preclinical disease models and PET ligands of different targets can be a powerful combination to assess the therapeutic potential of taVNS.

Evaluating phasic transcutaneous vagus nerve stimulation (taVNS) with pupil dilation: the importance of stimulation intensity and sensory perception

The efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive method to modulate physiological markers of noradrenergic activity of the Locus Coeruleus (LC), such as pupil dilation, is increasingly more discussed. However, taVNS studies show high heterogeneity of stimulation effects. Therefore, a taVNS setup was established here to test different frequencies (10 Hz and 25 Hz) and intensities (3 mA and 5 mA) during phasic stimulation (3 s) with time-synchronous recording of pupil dilation in younger adults. Specifically, phasic real taVNS and higher intensity led to increased pupil dilation, which is consistent with phasic invasive VNS studies in animals. The results also suggest that the influence of intensity on pupil dilation may be stronger than that of frequency. However, there was an attenuation of taVNS-induced pupil dilation when differences in perception of sensations were considered. Specifically, pupil dilation during phasic stimulation increased with perceived stimulation intensity. The extent to which the effect of taVNS induces pupil dilation and the involvement of sensory perception in the stimulation process are discussed here and require more extensive research. Additionally, it is crucial to strive for comparable stimulation sensations during systematic parameter testing in order to investigate possible effects of phasic taVNS on pupil dilation in more detail.

Molecular and Cellular Neurobiology of Spreading Depolarization/Depression and Migraine: A Narrative Review.

Migraine is a prevalent neurological disorder, particularly among individuals aged 20-50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies.