Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a sustained increase in phrenic motor output that arises from the balance of competing serotonin- and adenosine-driven mechanisms. Due to shifts in spinal adenosine levels, pLTF exhibits a diurnal cycle, where 15, 1-min hypoxic episodes elicit robust serotonin-dependent pLTF during the diurnal rest phase (∼130%) but are markedly attenuated in mid-active phase rats (∼30%) due to undermining effects from elevated spinal adenosine. Mechanistic studies of pLTF typically use anesthetized, paralyzed, mechanically ventilated rats with bilateral cervical vagotomy to prevent ventilator entrainment. However, vagotomy increases arterial pressure, which may protect spinal cord perfusion during hypoxic episodes. Here, we tested the hypothesis that intact vagus nerves diminish spinal oxygenation and pLTF expression. Rats with intact vagus nerves had lower arterial pressure and spinal cord oxygen tensions during hypoxic episodes, despite equivalent hypoxemia. As spinal cord hypoxia promotes adenosine accumulation, expected to constrain serotonin-driven pLTF, we hypothesized that intact vagal feedback blunts rest-phase pLTF and abolishes diurnal variations in response to AIH (15, 1-min episodes). With intact vagi, increased phrenic burst amplitude 90 min post-AIH was markedly attenuated in the mid-rest (43 ± 63% baseline), but not mid-active phase (43 ± 25%), suppressing the magnitude of diurnal variation. Cervical spinal delivery of the A2a receptor antagonist MSX-3 restored robust pLTF in both diurnal phases; selective A2a receptor knockdown within phrenic motor neurons enhanced pLTF during mid-rest but not mid-active phase. Thus, intact vagus nerves indirectly shift the spinal serotonin/adenosine balance during hypoxia, suppressing diurnal variations in pLTF magnitude.NEW & NOTEWORTHY Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF) via competing serotonin versus adenosine-driven signaling cascades. pLTF mechanisms are typically studied in anesthetized, vagotomized rats. We report in anesthetized rats that intact vagus nerves: 1) lower blood pressure and spinal oxygen tension during hypoxic episodes; 2) increase the adenosine constraint of serotonin-driven pLTF; and 3) abolish diurnal variations in pLTF magnitude. Thus, vagal feedback regulates pLTF via indirect effects on the spinal serotonin/adenosine balance.

Rett syndrome is a neurodevelopmental disorder caused by an X-linked mutation of the MeCP2 gene. Individuals with Rett syndrome, as well as rodent models of this disorder, demonstrate abnormal cortical responses to sound, which impair auditory discrimination ability. Vagus nerve stimulation (VNS) paired with tones has been shown to drive robust changes in the auditory cortex physiology of Mecp2+/- rats and has the potential to improve the communication abilities of individuals with Rett syndrome. The aim of this study was to describe the proteomic differences present in the auditory cortex of the Mecp2+/- rat model of Rett syndrome, as well as the molecular effect of VNS paired with tones. This study used global proteomic analysis of auditory cortex tissue taken from Mecp2+/- rats exposed to VNS paired with tones compared to untreated Mecp2+/- rats and wild-type (WT) littermate controls with no VNS exposure. Our results demonstrate dysregulation of mitochondrial and synaptic proteins in the Mecp2+/- rat auditory cortex. In addition, we show that VNS-tone pairing induces significant alterations to the auditory cortex proteome of Mecp2+/- rats by changing the expression of proteins involved in regulating synaptic vesicles and synaptic transmission. This work provides evidence of key mechanisms that may drive auditory processing dysfunction in Rett syndrome and demonstrates that VNS-tone pairing is sufficient to alter protein expression in the auditory cortex.

Vagus nerve stimulation (VNS) is a neuromodulatory intervention with antiinflammatory and autonomic regulatory properties. Although its clinical applications have primarily been explored in neurological disorders, its potential role in pulmonary and respiratory outcomes across preclinical and clinical settings remains incompletely characterized and dispersed across different study domains. This scoping review aimed to map the available evidence on the effects of VNS on the pulmonary and respiratory systems, with particular emphasis on inflammatory and autonomic mechanisms. This scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Three reviewers systematically searched PubMed, Web of Science, and the Cochrane Library for studies published between January 2020 and February 2026. Original preclinical and clinical studies investigating invasive or noninvasive VNS and reporting pulmonary, respiratory physiology, autonomic, or inflammatory outcomes were included. A total of 159 records were identified, of which 12 studies met the inclusion criteria. The evidence base was predominantly preclinical. In animal studies, invasive cervical VNS was frequently associated with reductions in pulmonary inflammation, histopathological lung injury, and proinflammatory cytokine expression. Clinical studies were limited and heterogeneous, but generally indicated variable modulation of autonomic function, including changes in parasympathetic activity, as well as heterogeneous effects on systemic inflammatory markers and limited respiratory outcomes. Current evidence suggests that VNS may modulate pulmonary inflammatory responses in preclinical models. However, clinical evidence remains limited and heterogeneous, particularly regarding autonomic and respiratory outcomes. Well-designed clinical trials using standardized stimulation protocols and predefined respiratory end points are needed to clarify its therapeutic potential in respiratory disorders.

Neuromodulation and sudden unexpected death in epilepsy: A systematic review of SUDEP rates across VNS, DBS, and RNS therapies.

The stress-myopia pathway: A pivotal hub in myopia pathogenesis.

To integrate mechanistic and clinical evidence on vagal regulation of immunity via the cholinergic anti-inflammatory pathway, linking neural and inflammatory signaling in rheumatoid arthritis (RA). It highlights how reduced vagal tone contributes to disease onset and progression and frames neuromodulation as a rationale for adjunctive therapeutic strategies. Preclinical and clinical data demonstrate that vagal efferent activity modulates immune responses through noradrenergic circuits and activation of α7-nicotinic-acetylcholine-receptors on immune cells, inhibiting NF-κB nuclear translocation and reducing pro-inflammatory cytokines. This neuroimmune axis interacts with the hypothalamic-pituitary-adrenal axis and the microbiome, supporting an integrated model of inflammation. Vagus nerve stimulation (VNS) has been associated with reductions in inflammatory markers and clinically meaningful improvements in patients with RA. Implantable VNS has demonstrated efficacy and has received regulatory approval for moderate-to-severe RA refractory to disease-modifying antirheumatic drugs; however, the available evidence remains limited and requires confirmation in larger and more diverse populations. Noninvasive approaches show favorable safety profiles but heterogeneous efficacy and currently lack regulatory approval for immune-mediated diseases. VNS represents a promising adjunct to conventional immunosuppressive therapy for RA. Further well-designed trials are needed to standardize stimulation protocols, and define optimal strategies for clinical implementation.

Physical exercise modulates T cell activity and mitigates synaptic dysfunction in multiple sclerosis through vagus nerve engagement.

Respiratory diseases, including bacterial pneumonia, viral infections and allergic asthma, are leading causes of hospitalization, yet current therapies often fall short. The lower airways are densely innervated by pain-transmitting sensory neurons (nociceptors) that arise from the nodose-jugular ganglia of the vagus nerve, with additional contributions from the spinal dorsal root ganglia. Converging evidence indicates that reciprocal neuroimmune signalling between lung-innervating sensory neurons and immune cells lies at the centre of pulmonary defence, inflammation and tissue repair. Among several immunomodulatory neuropeptides, calcitonin gene-related peptide (CGRP), released by activated TRPV1-positive nociceptors, has context-dependent functions. CGRP supports tissue protection and repair by shaping macrophage and neutrophil activation states, yet these same actions can exacerbate pathology during bacterial infection. In allergic asthma, pulmonary neuroendocrine cells act as early epithelial sentinels that amplify type 2 immunity and help todefine state-dependent effects of CGRP as well as other neuropeptides, including vasoactive intestinal peptide (VIP), neuromedin U (NMU) and substance P (SP). An updated framework that accounts for phase-specific and context-specific neuromodulation could enable new therapeutic strategies, including targeted inhibition or modulation of defined pathways to preserve essential reflexes while meaningfully altering disease trajectories and outcomes. Incorporating the neural state and exposure history will be critical for developing disease-modifying therapies informed by pulmonary neuroimmunology.

Insula modulation effects of transcutaneous auricular vagus nerve stimulation treating functional dyspepsia.

Transcutaneous vagus nerve stimulation enhances reward-effort efficiency in severe major depressive disorder

Post-stroke dysphagia (PSD) is a common and disabling complication of stroke. Conventional swallowing rehabilitation provides limited benefit for patients with moderate-to-severe PSD, especially those with impaired neuromuscular activation. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive neuromodulatory approach that may enhance swallowing recovery, yet its clinical efficacy and underlying mechanisms remain to be clarified. A total of 96 patients with PSD were randomly assigned to a control group (conventional swallowing rehabilitation) or a taVNS group (conventional rehabilitation + taVNS). After a 4-week intervention, 86 patients completed the study (Control: n = 44; taVNS: n = 42). Clinical swallowing outcomes (FOIS, SSA, PAS), swallowing-related surface electromyography (Aemg, Iemg, reverse activation proportion, EMG latency), and serum biomarkers (BDNF, GFAP, IL-6) were assessed before and after treatment. Both groups exhibited improved swallowing function after intervention; however, the taVNS group showed significantly greater improvement in FOIS (p < 0.001), SSA (p < 0.001), and PAS (p = 0.001) compared with the control group. The taVNS group also demonstrated larger increases in Aemg and Iemg, greater reductions in reverse activation proportion, and shorter EMG latency (all p < 0.05). Serum BDNF levels increased more prominently in the taVNS group, whereas GFAP and IL-6 levels showed significantly greater reductions (all p < 0.01), with large to moderate-large effect sizes for key outcomes (FOIS: Cohen's d = 0.69, 95%CI [0.42,0.82]; SSA: d = 0.64, 95%CI [-5.28,-1.74]; BDNF: d = 1.36, 95%CI [2.33,3.77]; IL-6: d = 0.91, 95%CI [-16.65,-7.99]). taVNS combined with conventional rehabilitation was associated with greater swallowing improvements. However, due to feasibility constraints in moderate-to-severe PSD patients, a sham control was not included; therefore, causal attribution specifically to vagus nerve activation remains preliminary. The observed changes in serum biomarkers (increased BDNF, decreased GFAP and IL-6) are exploratory parallel associations and do not constitute mechanistic proof of central nervous system effects.

This study aims to analyze differences in pre-implantation invasive electroencephalographic (IEEG) data between vagus nerve stimulation (VNS) responders (>50% seizure reduction) and VNS nonresponders (<50% seizure reduction). We retrospectively identified 19 patients with drug-resistant focal epilepsy who underwent IEEG followed by VNS implantation instead of resective brain surgery. Resting-state IEEG recordings (30 min) were selected for all patients. Three biomarkers were analyzed in the IEEG data: (1) the number of interictal epileptiform discharges (IEDs), (2) the number of high-frequency oscillations (HFOs; ripples: 80-250 Hz, fast ripples: 250-600 Hz), and (3) relative entropy (all frequency bands, 80-250 Hz, and 250-600 Hz). Analyses were performed in three regions of interest: (1) the all contact zones (ACZ), (2) the seizure-onset zones (SOZ), and (3) the non-seizure onset zones (NON SOZ). Differences between VNS responders and nonresponders were then evaluated. Finally, a statistical classifier was constructed to predict VNS efficacy based on all three biomarkers in the ACZ, SOZ, and non-SOZ. The only biomarker that revealed significant differences between VNS responders and nonresponders was Relative Entropy (SOZ: ripples [U = 1, p = 0.18] and fast ripples [U = 8.0, p = 0.009]), but analysis of effect size using Cliff's delta demonstrated large effects across all three zones in the raw signal, ripple, and fast ripple frequency bands. The best accuracy of 0.84 was obtained for the classifier based on the ACZ; the accuracy of the classifier for the SOZ and NON SOZ was 0.72 and 0.79, respectively. Invasive electroencephalographic recordings can be used to predict pre-implantation VNS efficacy. In this context, Relative Entropy appears to be a crucial biomarker for distinguishing between VNS responders and nonresponders. This study shows that brain recordings taken with internal electrodes can help doctors predict whether vagus nerve stimulation will successfully reduce a patient's seizures. We found that a specific measure of brain activity patterns, called Relative Entropy, is a key indicator of whether the treatment will be effective. These findings suggest that analyzing these brain signals can help identify the patients most likely to benefit from vagus nerve stimulation before the device is implanted.

Vagal Nerve Stimulation in Patients With Heart Failure and Reduced Ejection Fraction: The ANTHEM-HFrEF Trial.

Minimally invasive brain modulation is essential for understanding and treating neurological disorders. This study presents a wireless, optically controlled nitric oxide (NO)-releasing microbioelectronic device (ONMD) that enables peripheral-to-central neuromodulation without direct brain intervention. Upon light activation, the ONMD releases NO to locally activate transient receptor potential (TRP) channels, forming a confined NO-TRP signaling hub that selectively stimulates the vagus nerve and activates the nucleus tractus solitarius (NTS), a key brainstem center involved in autonomic and reward regulation. Through this hierarchical pathway, the ONMD-mediated neuromodulation alleviates depressive-like behaviors in mice, accompanied by reduced peripheral inflammation and restored central serotonin (5-HT) homeostasis. Operating in the intestine, the ONMD achieves remote modulation of central circuits through peripheral access. This gasotransmitter-mediated, multilevel bioelectronic approach offers a noninvasive strategy for regulating brain function and advancing neuropsychiatric therapies.

Treatment-resistant depression and chronic pain represent major global health challenges due to their high prevalence, significant disability burden, and limited response to conventional therapeutic approaches. Recent advances in neuroscience have improved understanding of the neural networks involved in emotional regulation, cognitive processing, and pain modulation, leading to the development of innovative neuromodulation strategies. This review analyzes current evidence regarding neurostimulation therapies used in the management of treatment-resistant depression and chronic pain, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation, deep brain stimulation, spinal cord stimulation, and dorsal root ganglion stimulation. A scientific-method-based literature review was conducted using publications indexed in major biomedical databases. The findings indicate that neurostimulation offers clinically meaningful benefits in selected patients by directly modulating dysfunctional neural circuits associated with symptom persistence. Repetitive transcranial magnetic stimulation demonstrated strong evidence in treatment-resistant depression, while spinal cord stimulation and dorsal root ganglion stimulation showed substantial effectiveness in refractory neuropathic pain conditions. The review also highlights the importance of individualized treatment selection, safety considerations, technological innovation, and multidisciplinary collaboration. Furthermore, emerging developments involving adaptive stimulation systems, artificial intelligence, biomarker-guided interventions, and precision neuromodulation may significantly influence future clinical practice. Neurostimulation is increasingly recognized as a valuable component of modern neurological, psychiatric, neurosurgical, and pain management strategies, with growing implementation across diverse healthcare systems, including Latin America. Continued research and technological advancement are expected to further expand its therapeutic potential and improve outcomes for patients with complex and refractory disorders.

Therapeutic approaches for functional Globus Pharyngeus: A systematic review of studies from 2000 to 2025.

Current disease-sensing devices primarily focus on distinguishing between healthy and diseased states, effective for diagnosis but limited in guiding optimal intervention timing for prevention. We developed a tripartite framework identifying pre-disease state in depression, a reversible phase preceding irreversible onset. Using complex systems theory, we analyzed early-warning signals emerging as biological systems approach critical transitions. Continuous monitoring of nine multimodal biomarkers-spanning electrophysiological, behavioral, and biological-enabled classification into normal, pre-disease, and disease states by quantitatively defining critical points. An artificial intelligence agent classified disease states with 95.2% accuracy using multimodal data, enabled by ultrasoft neural probes for stable, low-damage recordings. Therapeutic validation with a skin-attachable wireless vagus nerve stimulator integrating soft three-dimensional electrodes demonstrated superior efficacy during pre-disease states. Subjects treated during pre-disease showed faster recovery and greater therapeutic responses, while those treated after disease onset failed to achieve full recovery. This framework provides evidence-based rationale for early intervention.

Recent years have witnessed significant advances in neuromodulation techniques for stroke rehabilitation, especially in ameliorating motor deficits, positioning them as a key focus in both research and clinical practice. The selection of stimulation targets is crucial, as different sites engage distinct neural mechanisms and yield varied therapeutic outcomes. This review systematically synthesizes evidence from neuromodulation studies that target key regions, including the cerebral hemispheres, sensorimotor cortex, cerebellum, and vagus nerve. By analyzing the stimulation protocols, therapeutic effects, and optimal parameters associated with each target, we aim to provide a theoretical foundation and practical guidance for refining neuromodulation strategies in stroke rehabilitation.

High mobility group box 1 protein (HMGB1) is a central mediator of inflammation and pain, but efforts to neutralize it therapeutically have had limited clinical success. This gap suggests that the essential problem is not simply the abundance of extracellular HMGB1, but its accessibility: its availability to assemble into pathogenic complexes, engage receptors such as the receptor for advanced glycation end products (RAGE), enter cells, and deliver inflammatory cargo to the cytosol. Here, a perspective is advanced that integrates HMGB1 biology with the inflammatory reflex and the cholinergic anti-inflammatory pathway. In this framework, HMGB1 promotes inflammatory entry and amplification, whereas acetylcholine, acting through the vagus nerve and alpha7 nicotinic acetylcholine receptors, limits HMGB1 release and uptake of HMGB1-containing complexes. Vagus nerve stimulation therefore emerges as a bioelectronic strategy to restrict upstream access of danger signals to intracellular inflammatory pathways, in addition to suppressing downstream cytokine signaling. This formulation does not alter the established biology of HMGB1; rather, it places existing observations into a unifying model with direct relevance to inflammation and pain.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive technique engaging vagal afferents that may enhance cognition, but results vary across domains and samples. Following PRISMA, seven databases (inception-October 2025) plus registries and gray literature were searched. Random-effects meta-analyses (REML; Hedges' g) were complemented by Bayesian hierarchical models and sensitivity analyses. Fifty-three studies were included; 30 contributed quantitative data (>1,500 participants). taVNS was associated with improved cognitive performance overall (g=0.41, 95% CI: 0.30-0.53; I2=51.4%). Effects were moderate for executive functions (g=0.46, 95% CI: 0.27-0.65; I2=9.5%) and cognitive flexibility/learning (g=0.53, 95% CI: 0.32-0.75; I2=52.9%), and small for working memory/attention (g=0.19, 95% CI: 0.04-0.33; I2=14.9%). Social cognition/emotion regulation showed larger but imprecise effects (k=3; g=0.80, 95% CI: 0.07-1.52; I2=82.1%). Clinical samples benefited similarly (k=7; g=0.55, 95% CI: 0.31-0.79; I2=29.5%), with no difference from healthy cohorts (β=-0.001, p=.994). High-intensity protocols (>1.0mA) yielded larger effects; mode, duration, and site were not moderators. Bayesian models supported effects (P [μ>0]≥0.93). taVNS is associated with statistically significant improvements in cognitive performance, strongest for executive control and adaptive learning. We propose a Vagal Neurocognitive Integration Model linking LC-NE arousal modulation to prefrontal control. Future diagnosis-specific, adequately powered trials with multimodal neuroimaging should refine mechanisms and dose-response.