Search Results (341)

Pain in children and adolescents remains an underestimated and undertreated condition, with long-term physical and psychosocial consequences. Non-invasive neuromodulation has emerged as a promising, low-risk approach for managing acute and chronic pain by modulating central and peripheral neural pathways. This systematic review followed PRISMA 2020 guidelines to evaluate the efficacy, safety, and clinical applicability of non-invasive neuromodulation techniques in pediatric pain. Searches were conducted in PubMed, Embase, Scopus, Web of Science, Cochrane CENTRAL, and ScienceDirect for randomized controlled trials (RCTs) published between 2015 and 2025. Six RCTs met the inclusion criteria, encompassing percutaneous electrical nerve field stimulation (PENFS), transcutaneous auricular vagus nerve stimulation (taVNS), transcutaneous electrical acupoint stimulation (TEAS), and transcutaneous electrical nerve stimulation (TENS). Four trials reported significant reductions in pain intensity alongside improvements in functional outcomes and quality of life, particularly in functional abdominal pain and postoperative contexts. Most studies showed low or moderate risk across domains, with appropriate randomization and blinded assessment. No serious adverse events were reported, confirming an excellent safety profile. These findings support non-invasive neuromodulation as a feasible and well-tolerated adjunct to conventional pediatric pain management. Further high-quality trials are warranted to standardize protocols and explore mechanisms of neuroplasticity in the developing nervous system. PROSPERO (CRD420251170866). Full article

Background: Currently, there is a considerable number of studies addressing vagus nerve stimulation (VNS) for the treatment of different stroke-related outcomes. We aimed to promote a broad view of the outcomes studied and what are the opportune outcomes to be studied involving this therapeutic strategy for the treatment of post-stroke complications. Methods: This is a scoping review that followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two investigators conducted independent searches on PubMed/MEDLINE, Scopus, and Embase till July 2025. Randomized clinical trials and preclinical studies using invasive or non-invasive vagus nerve stimulation conducted with a population diagnosed with stroke were included. Results: Forty-one experimental studies and sixteen clinical trials were included. The outcomes found were neuroprotection; motor, functional, and cognitive rehabilitation; dysphagia; comparison of different stimulation intensities; safety, efficacy, and feasibility of the non-invasive approach; comparison between transcutaneous auricular vagus nerve stimulation (taVNS) and transcutaneous cervical vagus nerve stimulation (tcVNS); and comparison between two models of ischemia (permanent and transient). Preclinical studies mostly investigated molecular elements involved in neuroprotection, neuroinflammation, and cellular apoptosis, while clinical studies evaluating the effectiveness of this technique used for rehabilitation and its comparison or combination with other techniques remain scarce. Conclusions: Most studies investigating the effects of VNS on different post-stroke outcomes are experimental studies. Clinical studies are still scarce and with limited analysis of outcomes. Full article

For decades, researchers have explored the therapeutic potential of the vagus nerve through vagus nerve stimulation (VNS). Initially developed for epilepsy, VNS has since been applied to treat resistant depression, stroke recovery, and inflammatory conditions. Transcutaneous VNS (tVNS) now offers a noninvasive alternative, fueling clinical trials in disorders ranging from rheumatoid arthritis and migraines to long COVID-19. Mechanistic studies suggest that afferent and efferent vagal fibers modulate immune responses, mood regulation, and neurotransmitter systems. The SPARC initiative has accelerated mapping of vagal circuits, enabling more precise approaches to stimulation. Despite progress, the results remain mixed: while some patients experience lasting symptom relief, others respond no better than to placebo. Depression studies, in particular, highlight both the promise and the complexity of VNS, as inflammation, motivation circuits, and gut–brain signaling emerge as key modulators. Next-generation closed-loop devices and circuit-specific targeting may improve efficacy and reduce adverse effects. VNS research thus lies at the intersection of neuromodulation, psychiatry, and immunology—offering hope for hard-to-treat conditions, yet demanding rigorous trials to separate myths from medicine. In this article, we review the current clinical and experimental applications of tVNS, analyze its mixed efficacy across psychiatric, immunological, and neurological disorders, and highlight the mechanistic insights, stimulation parameters, and emerging technologies that may shape next-generation therapies. Full article

Introduction: Stroke is a leading cause of adult-onset disability. Non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcutaneous vagus nerve stimulation (tVNS) are promising adjuncts to upper limb rehabilitation. The use of functional neuroimaging through task functional MRI (fMRI) or functional near-infrared spectroscopy (fNIRS) allows the visualisation of cortical activation patterns associated with stroke-related impairment and recovery. The present study comprehensively reviews the evidence base for the effects of NIBS on clinical and functional neuroimaging outcomes after stroke. Methods: Systematic searches were carried out in MEDLINE and EMBASE via Ovid. Inclusion criteria were clinical trials of adults with stroke and arm weakness undergoing NIBS, with clinical measures of arm function and neuroimaging outcome measures that included either task fMRI or task fNIRS. Two authors independently carried out study screening, risk of bias assessments, and data collection for clinical and neuroimaging outcomes pre- and post-intervention. Results: A total of 17 studies (12 rTMS, 5 tDCS), including 495 participants, met the inclusion criteria. Fifteen studies used task fMRI and four used task fNIRS. Improvements in arm-related motor activity were observed following both rTMS and tDCS. Most studies reported increased activation in ipsilesional sensorimotor areas alongside reductions in contralesional activation. Discussion: rTMS and tDCS may improve upper limb recovery in people with stroke. The increase in the laterality index towards activation of the ipsilesional hemisphere suggests that these NIBS techniques may facilitate neural reorganisation and restoration of motor networks in the affected hemisphere. Full article

Background/Objectives: Migraine is a complex neurological headache disorder, and transcutaneous auricular vagus nerve stimulation (taVNS) can effectively relieve headache symptoms, but its mechanism of effect is still unclear. This study aimed to explore the regulatory effects of taVNS on the locus coeruleus (LC) and the norepinephrine (NE) system in migraine mice. Methods: C57/BL6 mice were randomly assigned to four experimental groups: the control group, model group, taVNS group, and sham taVNS group. A migraine model was established by administration of nitroglycerin. Headache behaviors were assessed using the orofacial stimulation test (OST) and the mouse grimace scale (MGS). Immunofluorescence staining was conducted to evaluate the expression of NE neurons in the LC, while Western blotting was used to determine the expression levels of α-2A adrenergic receptors in the spinal trigeminal nucleus caudalis (Sp5C). Additionally, fiber-optic recording was employed to monitor the real-time dynamics of NE release in Sp5C. Results: After taVNS intervention, the drinking time of OST in the model mice was significantly prolonged(p < 0.05), and facial expression scores were reduced (p < 0.05). TaVNS increased the number of NE neurons in the LC (p < 0.05), promoted the release of NE in Sp5C (p < 0.05), and upregulated the expression of α-2A adrenergic receptors in Sp5C (p < 0.05). Conclusions: The analgesic effects of taVNS are related to the activation of the LC-NE system and the inhibition of the decrease in Sp5C in migraine mice. Full article

Background: Chronic pain conditions such as fibromyalgia syndrome (FMS) reflect maladaptive network physiology across perceptual–autonomic–immune axes, yet most treatments remain symptomatic and incompletely effective. Methods: We conducted a comprehensive systematic review to evaluate vagus nerve stimulation (VNS) and FMS within a network physiology framework. PubMed, Embase, and Cochrane CENTRAL were searched on October 24, 2025. Risk of bias was assessed using the ROB-2 tool. An iterative thematic synthesis was performed to develop an integrative conceptual framework and to identify knowledge gaps and future research directions. Results: We first summarize physiological evidence showing autonomic imbalance (e.g., decreased heart rate variability), neuroinflammatory activation, and aberrant cortical network connectivity in FMS, supporting a network-dysregulation model. We then included 6 studies (4 clinical studies and 2 protocols) on VNS effects, highlighting improvements in pain, fatigue, sleep disturbance and autonomic regulation, along with emerging mechanistic insights. Key methodological heterogeneity—such as stimulation parameters, outcome metrics, type of control arm, sham definition, and small samples—limits current interpretability. Finally, we outline a research agenda centered on network-based biomarkers, immunophenotyping, adaptive trial designs and stratification of responders, with the aim of validating taVNS as a scalable neuromodulatory intervention for FMS. Conclusions: By reframing FMS from a symptom-centric pharmacologic model to a network-centric neuromodulation approach, taVNS is a promising tool for mechanism-based therapeutics in central sensitization syndromes and chronic pain. Full article

Development of new therapeutic approaches and strategies for common neuropsychiatric disorders, including Major Depressive Disorder, anxiety disorders, and Post-Traumatic Stress Disorder, represent a significant global health challenge. Recent research indicates that emotional dysregulation and persistent inflammation are closely linked and serve as key pathophysiological features of these conditions. Emotional dysregulation is mechanistically coupled to locus coeruleus and norepinephrine (LC-NE) or noradrenergic system activity. Stemming from chronic stress, persistently elevated activity of the LC-NE system leads to hypervigilance, anxious states, and depressed mood. Concurrently, these symptoms are marked by systemic inflammation as indicated by elevated pro-inflammatory cytokines, and central neuroinflammation indicated by microglial activation in brain regions and networks involved in mood regulation and emotional control. In turn, chronic inflammation increases sympathetic tone and LC-NE activity resulting in a vortex of psychoneuroimmunological dysfunction that worsens mental health. Transcutaneous auricular vagus nerve stimulation (taVNS) in a non-invasive neuromodulation method uniquely positioned to address both noradrenergic dysfunction and chronic inflammation in neuropsychiatric applications. Evidence spanning the past decade demonstrates taVNS works via two complementary mechanisms. An ascending pathway engages vagal afferents projecting to the LC-NE system in the brain stem, which has been shown to modulate cortical arousal, cognitive function, mood, and stress responses. Through descending circuits, taVNS also modulates the cholinergic anti-inflammatory pathway to suppress the production of pro-inflammatory cytokines like TNF-α and IL-6 mitigating poor health outcomes caused by inflammation. By enhancing both central brain function and peripheral immune responses, taVNS has shown significant potential for recalibrating perturbed affective-cognitive processing. The present article describes and discusses recent evidence suggesting that taVNS offers a promising network-based paradigm for restoring psychoneuroimmunological homeostasis in common neuropsychiatric conditions. Full article

Objectives: The objective is assessing whether the placebo effect can influence the time course of recovery following a football match. Methods: Using a randomized crossover design, eighteen youth male players (age: 15.3 ± 0.5 years, stature: 178.7 ± 6.4 cm, body mass: 65.3 ± 7.6 kg, playing experience: 8.6 ± 1.5 years) completed two friendly matches, followed by placebo (PLA; sham vagus nerve stimulation) or passive rest (CON). To assess the impact of PLA, countermovement jump height (CMJ), 10 and 20 m sprint times, heart rate variability (Ln-rMSSD), static and dynamic muscle soreness, and perceived fatigue were measured at pre-match, post-match, post-recovery, and 24 h post-match. Results: Our findings indicate that match play induced substantial fatigue, with significant deteriorations [p ≤ 0.002, small-to-large effect sizes (ES)] in CMJ, 10 and 20 m sprint performance, Ln-rMSSD, muscle soreness, and perceived fatigue at post-match and post-recovery compared to pre-match (except Ln-rMSSD between pre-match and post-recovery: p = 0.151, small ES). Although no significant between-intervention differences were found for any variable at any time point (p > 0.05), effect size analysis showed moderately lower perceived fatigue (r = 0.40) and dynamic soreness (r = 0.32) in PLA compared to CON at post-recovery. Conclusions: These findings suggest that while placebo stimulation did not affect performance or heart rate variability, it may support perceptual recovery. This holds relevance for both research and practice, as including placebo conditions can help isolate psychological effects from true treatment responses, while promoting positive expectations may enhance the perceived effectiveness of recovery strategies. Full article

Cardiac amyloidosis (CA) is an increasingly recognized cause of restrictive cardiomyopathy in which extracellular amyloid deposition leads to progressive structural and functional impairment. Beyond myocardial infiltration, growing evidence highlights the central role of autonomic nervous system dysfunction (ANS) —particularly the vagal nerve involvement—as a contributor to orthostatic intolerance, syncope, exercise limitation, arrhythmias, and reduced quality of life. Emerging data suggest that autonomic impairment may precede overt cardiac manifestations, offering a potential window for earlier recognition. This narrative review summarizes current knowledge on the mechanisms and clinical relevance of autonomic dysfunction in CA, emphasizing the novelty of the “vagal link” as a unifying framework connecting with a specific focus on the vagus nerve (VN) and its complex interplay with cardiac structure and function. We further discuss diagnostic approaches and the potential role of autonomic assessment in early detection, risk stratification, and personalized treatment strategies. A clearer understanding of vagal dysfunction may provide new insights into disease progression and identify opportunities for therapeutic innovation. Full article

Introduction: Refractory Status Epilepsy Syndrome is a heterogeneous group of diseases associated with status epilepsy. Literature and definition have been conflicting and confusing in terms of their nomenclatures. New-onset refractory status epilepticus (NORSE) is a syndrome characterized by new onset refractory seizures in a previously health child. Febrile infection-related epilepsy syndrome (FIRES) is a similar syndrome now considered a variant of NORSE and is defined as a febrile event taking place between twenty-four hours and two weeks prior to the commencement of refractory status epilepticus. An autoimmune or inflammatory etiology is often implied in both conditions because infection is rarely identified. Aim: This review provides an update on hypotheses, etiology, pathophysiology, clinical features, diagnosis, laboratory evaluation, treatment, and perspectives for NORSE/FIRES. Methods: A PubMed Clinical Queries search is performed using keywords of NORSE and FIRES, on human subjects up to May 2025. All reviews, systematic reviews, case series and case reports were included. Results: Seizures are typically recalcitrant in NORSE/FIRES. Treatments include anti-seizure medications (ASM), ketogenic diet, immunotherapy (intravenous immunoglobulin ± plasmapheresis ± corticosteroid). The prognosis is usually poor. Most children would suffer refractory epilepsy and associated cognitive impairment if they survived. Guidelines and new consensus on NORSE/FIRES terminology have aided clinicians in managing status epilepticus in a previously healthy child that occurs ± a minor febrile episode. When an autoimmune or paraneoplastic condition is subsequently identified, the condition will be named accordingly. Conclusions: NORSE and FIRES are similar conditions except that vagus nerve stimulation appears to be more efficacious in NORSE than FIRES. We propose to define these heterogeneous and confusing conditions as “NOSES” as a two-criteria syndrome: New Onset + Status Epilepticus Syndrome, lasting for over 24 h despite the use of two standard ASM. Autoimmune, paraneoplastic and infectious encephalitis are specific diagnoses of NOSES with etiology subsequently identified. Full article

The liver is intricately innervated by sympathetic, parasympathetic, and sensory fibres, forming a dynamic neurovascular and neuroimmune network that regulates hepatic function and contributes to disease pathogenesis. While traditionally underexplored, hepatic innervation is now recognised as a key modulator of metabolic homeostasis, immune surveillance, and vascular tone. Historically, the liver was not considered a major target of neural regulation, but recent advances in neurology and imaging have revealed complex and dynamic interactions between neural circuits and hepatic functions. This review provides a comprehensive overview of liver innervation, detailing its anatomical organisation and functional roles in both physiological and pathological contexts. We investigate the role of liver innervation in shaping immune responses, particularly in the context of metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and autoimmune liver diseases, including autoimmune hepatitis and primary biliary cholangitis. Special attention is given to the neuroimmune crosstalk that governs inflammation, fibrosis, malignancy, and tissue remodelling. Furthermore, we examine how neural inputs influence hepatic blood flow, sinusoidal endothelial function, and portal hypertension, highlighting the interplay between neural and vascular systems. We highlight neuromodulatory approaches, including vagus nerve stimulation and other agents to modulate liver inflammation, vascular dysfunction, and immune dysregulation. Finally, we discuss emerging research models, including liver organoids, Artificial Intelligence-based digital twins and biomaterials as innovative platforms designed to study neural-liver interactions and test new therapeutic strategies. By integrating neuromorphology, immunology, and hepatology, this review aims to advance our understanding of liver innervation as a central player in hepatic health and disease and to identify novel targets for therapeutic intervention. Full article

It has been demonstrated that prolonged exposure to stress engenders a plethora of neuropsychiatric, immune and metabolic disorders. However, its pathophysiology transcends the conventional hypothalamic–pituitary–adrenal (HPA) axis. This review addresses the central question of how integrated neural and microbial pathways regulate stress responses and resilience. We present a model in which the parasympathetic nervous system (particularly the vagus nerve) and the gut microbiota interact to form a bidirectional neuroimmune network that modulates the HPA axis, immune function, neurotransmitter balance, and metabolic adaptation. Key molecular pathways include nitric oxide synthesis via the classical nitric oxide synthase (NOS)-dependent and microbiota-mediated nitrate–nitrite routes, inducible nitric oxide synthase (iNOS) regulation, nuclear factor erythroid 2-related factor 2 (Nrf2) signalling, lysosomal function, autophagy and the cholinergic anti-inflammatory reflex. Other pathways include the gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signalling, polyamine metabolism and peroxisome proliferator-activated receptor gamma (PPARγ). Intermittent hypoxia training (IHT) enhances mitochondrial function, oxidative stress responses, autonomic balance and gut microbiota composition. This promotes parasympathetic activity and stress resilience that is tailored to the individual. These adaptations support the concept of personalised stress response profiles based on hypoxic adaptability. Clinical implications include combining IHT with vagus nerve stimulation, probiotics, dietary strategies, and stress reduction techniques. Monitoring vagal tone and microbiota composition could also serve as predictive biomarkers for personalised interventions in stress-related disorders. This integrative framework highlights the therapeutic potential of targeting the parasympathetic system and the gut microbiota to modulate stress. Full article

The medical discourse entails the analysis of the modalities, which are far from unbiased, by which hypotheses and results are laid out in the dissemination of findings in scientific publications. This gives different emphases on the background, relevance, robustness, and assumptions that the audience takes for granted. This concept is extensively studied in socio-anthropology. However, it remains generally overlooked within the scientific community conducting the research. Yet, analyzing the discourse is crucial for several reasons: to frame policies that take into account an appropriately large screen of medical opportunities; to avoid overseeing promising but less walked paths; to grasp different types of representations of diseases, therapies, patients, and other stakeholders; to understand how these terms are conditioned by time and culture. While socio-anthropologists traditionally use manual curation methods–limited by the lengthy process–machine learning and AI may offer complementary tools to explore the vastness of an ever-growing body of medical literature. In this work, we propose a pipeline for the analysis of the medical discourse on the therapeutic approaches to rheumatoid arthritis using topic modeling and transformer-based emotion and sentiment analysis, overall offering complementary insights to previous curation. Full article

Vagus Nerve Stimulation (VNS) therapy is a neuromodulation technique useful for the treatment of drug-resistant epilepsy and treatment-resistant depression. This article begins by reviewing the neuroanatomy and physiology of the vagus nerve. It then delves into recent advances in our understanding of VNS’s mechanism of action at different levels: how it affects different nerve fibers, how it affects neural pathways, and how it creates anti-inflammatory effects. This article then surveys research to adapt and optimize VNS, guided by an improved understanding of its mechanism of action and descriptions of its effects. Full article

The rising prevalence of neuroimmune disorders such as multiple sclerosis and fibromyalgia has renewed interest in the hygiene hypothesis, which posits that reduced early-life microbial exposure deprives the immune system of formative “noise” that calibrates thresholds of tolerance. We extended this framework by introducing stochastic resonance (SR), a system phenomenon in which optimally tuned noise enhances weak-signal detection in nonlinear networks, as a potential surrogate for missing microbial variability. As electrical noise and subthreshold stimulation have been shown to modulate cortical excitability and enhance perception, microbial noise may be necessary for sustaining immune plasticity. Conversely, a lack of stimulation, whether microbial or electrical, can lead to maladaptive states characterized by dysregulated signaling and heightened vulnerability to chronic inflammation. Evidence from immunology highlights noise-aware processes, such as T-cell receptor proofreading, NF-κB pulsatility, and cytokine quorum sensing, all of which exploit stochastic fluctuations. Computational tumor–immune models similarly suggest that tuned noise can optimize immune surveillance. Clinical data from neuroscience demonstrate that subsensory electrical noise improves motor excitability and sensory perception, whereas vagus nerve stimulation modulates inflammatory pathways, underscoring translational feasibility. We propose that SR reframes noise from a biological error to a therapeutic resource capable of recalibrating dysregulated neuroimmune thresholds. This conceptual synthesis positions microbial and electrical noise as parallel modulators of tolerance and outlines testable predictions with translational potential for neuroimmune disorders. Full article