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Tiagabine has been associated with reports of status epilepticus as well as encephalopathy, even when used within therapeutic doses. Vagus nerve stimulation (VNS) has been used successfully to reduce seizure frequency in the outpatient setting as well as in the acute setting of status epilepticus. It is also theorized to reduce cortical synchronization. We present a case of a patient on adjunctive tiagabine therapy who developed sudden onset encephalopathy and rhythmic delta activity soon after vagus nerve stimulation was turned off in preparation for magnetic resonance imaging. The bilateral rhythmic delta activity significantly reduced in burden after VNS was turned back on and encephalopathy also gradually improved to baseline. We hypothesize that vagus nerve stimulation successfully interrupted diffuse hypersynchrony, in the form of bilateral rhythmic delta activity, caused by tiagabine. To our knowledge, this is the first report of such a phenomenon.

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BACKGROUND: Gut microbiota dysbiosis is closely associated with psychiatric disorders such as depression and anxiety (DA). In our preliminary study, fecal microbiota transplantation from volunteers with psychological stress and subclinical symptoms of depression (Vsd) induced DA-like behaviors in mice. Escherichia fergusonii (Esf) was found to be more abundant in the feces of Vsd compared to healthy volunteers. Therefore, we investigated the effect of Esf on DA-like behavior and neuroinflammation in mice with and without celiac vagotomy. METHODS AND RESULTS: Orally gavaged Esf increased DA-like behaviors, tumor necrosis factor (TNF)-α, and toll-like receptor-4 (TLR4) expression, and NF-κB+Iba1+ and lipopolysaccharide (LPS)+Iba1+ cell populations, while decreasing serotonin, 5-HT1A receptor, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex. However, celiac vagotomy attenuated Esf-induced DA-like behavior and neuroinflammation. Orally gavaged extracellular vesicle (EV) from Vsd feces (vfEV) or Esf culture (esEV) induced DA-like behavior and inflammation in hippocampus, prefrontal cortex and colon. However, celiac vagotomy attenuated vfEV- or esEV-induced DA-like behaviors and inflammation in the brain alone, while vfEV- or esEV-induced blood LPS and TNF-α levels, colonic TNF-α expression and NF-κB-positive cell number, and fecal LPS level were not. Although orally gavaged fluorescence isothiocyanate-labeled esEV was translocated into the blood and hippocampus, celiac vagotomy decreased its translocation into the hippocampus alone. CONCLUSIONS: esEVs may be translocated into the brain via the vagus nerve and bloodstream, subsequently inducing TNF-α expression and suppressing serotonin, its receptor, and BDNF expression through the activation of TLR4-mediated NF-κB signaling, thereby contributing to DA pathogenesis.

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AIMS: Transcutaneous auricular vagus nerve stimulation (taVNS) is widely used to treat a variety of disorders because it is noninvasive, safe, and well tolerated by awake patients. However, long-term and repetitive taVNS is difficult to achieve in awake mice. Therefore, developing a new taVNS method that fully mimics the method used in clinical settings and is well-tolerated by awake mice is greatly important for generalizing research findings related to the effects of taVNS. The study aimed to develop a new taVNS device for use in awake mice and to test its reliability and effectiveness. METHODS: We demonstrated the reliability of this taVNS device through retrograde neurotropic pseudorabies virus (PRV) tracing and evaluated its effectiveness through morphological analysis. After 3 weeks of taVNS application, the open field test (OFT) and elevated plus maze (EPM) were used to evaluate anxiety-like behaviors, and the Y-maze test and novel object recognition test (NORT) were used to evaluate recognition memory behaviors, respectively. RESULTS: We found that repetitive taVNS was well tolerated by awake mice, had no effect on anxiety-like behaviors, and significantly improved memory. CONCLUSION: Our findings suggest that this new taVNS device for repetitive stimulation of awake mice is safe, tolerable, and effective.

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Renal denervation (RDN) has been used for treating resistant hypertension. A few recent studies show vagal innervation of kidneys causing confusion. This study aimed to provide anatomical and functional evidence for renal autonomic innervation. Experiments were performed in male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Pseudorabies virus (PRV) in paraventricular nucleus and rostral ventrolateral medulla was prevented by bilateral RDN, but not subdiaphragmatic vagotomy. PRV did not appear in dorsal motor nucleus of vagus and nucleus tractus solitarii 72 h after renal injection of PRV. Adrenergic fibers were approximately 7 times more than cholinergic fibers in main renal artery (MRA) and its first (1RA) and second grade (2RA) branches. Adrenergic fibers in 1RA were more than these in MRA and 2RA. Tyrosine hydroxylase immunoreactivity in these arteries was higher in SHR than WKY. Norepinephrine (NE) increased, and α-receptor antagonist reduced vascular ring tension of renal arteries. The effect of NE was greater in 1RA and 2RA than MRA, which was prevented by α-receptor antagonist. Acetylcholine (ACh) or blockage of ß-receptors, M- or N-receptors had no significant effects on vascular ring tension and the effect of NE. Renal blood flow was reduced by electrical stimulation of renal nerves, but not affected by stimulation of subdiaphragmatic vagus. These results provide anatomical and functional evidence that kidneys are innervated and renal blood flow is regulated by renal sympathetic nerves rather than vagus. Renal vasoconstriction is regulated by NE and adrenergic fibers rather than ACh or cholinergic fibers in WKY and SHR.

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BACKGROUND: Vagal schwannomas are well-documented, but cervical sympathetic chain schwannomas (CSCS) are rare, with most knowledge from case reports. This study aims to identify radiological predictors of misdiagnosis and factors guiding surgical approaches based on tumor size and extent. METHODS: An ambispective analysis was conducted on 21 cases of CSCS, examining preoperative data, intraoperative findings and the questionnaire to identify the potential predictors. Tumors were classified into three types based on their relationship with the carotid sheath, and this classification was correlated with vessel ligation and postoperative neural outcomes. RESULTS: An excellent agreement was found between radiologist on new classification system(Kappa:0.89). Tumor classification revealed a diverse distribution, with 6 cases identified as Type 1, 6 as Type 2, 5 as Type 3, and 4 as Type 3S. The necessity of external carotid artery (ECA) ligation correlated with the tumor type. Type 3 tumors required ECA ligation in 50% of cases, while Type 1 and Type 2 tumors predominantly involved vascular preservation. Postoperative complications included vagal palsy in 28.5% of cases and first bite syndrome in 71.4%. CONCLUSION: Accurate preoperative planning and a novel staging system can enhance surgical outcomes and reduce postoperative complications as validated by our study.

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Objective This study aims to develop a quantifiable model for evaluating the outcomes of vagus nerve stimulation (VNS) in patients with multifocal refractory epilepsy, particularly focusing on those who have undergone multiple surgeries. By adopting a patient-centered approach, the study seeks to provide a robust framework for assessing VNS efficacy across various patient demographics, including both adult and pediatric patients, and those with impaired cognitive and communicative abilities. Methods We conducted a retrospective analysis of 49 patients with multifocal refractory epilepsy who underwent at least one VNS surgery. The cohort was divided into two groups: adults (≥16 years) and a combined pediatric group that included patients under 16 years of age and patients with impaired cognitive and communicative skills. The Liverpool Seizure Severity Scale (LSSS) was used for adults, while the Hague Seizure Severity Scale (HASS) was employed for the pediatric group. Key outcome measures, including changes in seizure frequency, quality of life (QoL), number of hospitalizations, and other clinical metrics, were quantified using our proposed model. The iterative use of the mentioned scales was also assessed for validity by comparison with the Engel Outcome Scale (EOS). A total of 96 procedures were assessed. Results The results indicated a significant reduction in seizure severity post-surgery across both groups, as quantified by the LSSS for adults and HASS for pediatric and cognitively impaired patients. The model also demonstrated a consistent decrease in seizure frequency and an improvement in QoL metrics over successive surgeries. Minimal major side effects were reported, supporting the effectiveness of our quantification approach in capturing VNS outcomes. Conclusions This study introduces a novel, quantifiable model for evaluating VNS outcomes, providing a comprehensive tool for clinicians to assess the effectiveness of VNS in managing multifocal refractory epilepsy. By integrating multiple outcome measures into a cohesive framework, our model can aid in better understanding VNS therapy's impact and contribute to more informed clinical practice.

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Background: Vagal paragangliomas (VPs) are rare tumors in the upper cervical region. Although surgical resection is the standard treatment for these tumors, it carries significant risks due to the tumor's high vascularity and proximity to vital structures. Stereotactic radiosurgery (SRS) for skull base paraganglioma could be a minimally invasive alternative. Case Description: We report the case of a 47-year-old man with a large, asymptomatic VP who was successfully treated with SRS with Gamma Knife Icon, which was performed in the parapharyngeal space (volume: 25.7 mL) using a marginal dose of 14 Gy to the 45% isodose line. This case illustrates the successful treatment of a lesion near the conventional limits (lower limit of C2 vertebral body) using noninvasive mask fixation. Excellent tumor control without neurological deficits was achieved for 25 months after SRS. The tumor volume decreased by 70% (final volume: 7.6 mL). Conclusion: This study demonstrates the utility of Gamma Knife Icon, which facilitates optimal SRS for upper cervical lesions, including VPs.

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Background: Gross motor function impairments and manual dexterity deficits are frequently observed in children and adolescents with Cerebral Palsy (CP), having a major impact on their activity level and autonomy. Improving manual dexterity and activity level of patients with CP is often the focus of rehabilitation. Novel and adjuvant treatment methods that could support the standard training also in chronic conditions are a research priority. The transcutaneous Vagus Nerve Stimulation (tVNS) is a non-invasive brain stimulation technique, which provides a bottom-up stimulation of subcortical and cortical brain structures, enhancing brain GABA and Noradrenaline levels. This technique may play a pivotal role in brain plasticity, which has not been tested in CP patients before. Methods: 44 children and adolescents with CP will be involved, treated in pairs in a randomized, double-blind, pre-post test study. The two groups will undergo the Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) for 2 consecutive weeks, with 3 h daily sessions for 5 days per week, for an overall time interval of 30 h; the training will be combined with the application for 75 min/day of active or sham tVNS, in separate, randomly allocated groups. The primary outcome measure will include the scores at the Assisting Hand Assessment and Box and Block Test, and at an ad-hoc visuomotor task evaluating manual visuomotor control. Secondary outcomes will include the scores at the Children's Hand Experience Questionnaire, Canadian Occupational Performance Measure, Melbourne Assessment of Unilateral Upper Limb Function, Gross Motor Function Measure, Vineland, Pediatric quality of life inventory. The evaluation points will include pre (T0), post (T1) and 3-month follow up (T2) assessments. Safety and tolerability will also be assessed. Results: The results of this trial will assess whether tVNS can effectively boost the effects of an intensive two-week bimanual training, in improving manual dexterity in children and adolescents with cerebral palsy, ensuring safety and tolerability throughout the intervention period.Clinical trial registration: ClinicalTrials.gov, NCT06372028.

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Nearly all geriatric surgical complications are studied in the context of a single organ system, e.g., cardiac complications and the heart; delirium and the brain; infections and the immune system. Yet, we know that advanced age, physiological stress, and infection all increase sympathetic and decrease parasympathetic nervous system function. Parasympathetic function is mediated through the vagus nerve, which connects the heart, brain, and immune system to form, what we have termed, the brain-heart-immune axis. We hypothesize that this brain-heart-immune axis plays a critical role in surgical recovery among older adults. In particular, we hypothesize that the brain-heart-immune axis plays a critical role in the most common surgical complication among older adults: postoperative delirium. Further, we present heart rate variability as a measure that may eventually become a multi-system vital sign evaluating brain-heart-immune axis function. Finally, we suggest the brain-heart-immune axis as a potential interventional target for bio-electronic neuro-immune modulation to enhance resilient surgical recovery among older adults.

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PURPOSE: Trauma has the potential to cause haemorrhage, tissue damage, pain, visceral manipulation and psychological distress. Each of these consequences of trauma can cause changes in autonomic outflow, which dictates a patient's vital signs. Patients who are hypotensive and bradycardic due to a vagally mediated parasympathetic response to pain, psychological distress and visceral manipulation may be confused with those who exhibit bradycardia and hypotension following significant blood volume loss. METHODS: This review summarises literature that describes specific stimuli, patterns of injury and patient characteristics that are associated with a non-haemorrhagic vagal response to trauma. RESULTS: Twenty-six records described predominantly parasympathetic responses to trauma (both blunt and penetrating) and surgery ("iatrogenic trauma"). Such a non-haemorrhagic vagal response occurs following a wide variety of injury patterns. Patient age and sex are poor predictors of the likelihood of a non-haemorrhagic vagal response. The development and resolution of a non-haemorrhagic vagal response occurs over a heterogenous time period. It is unclear whether speed of onset and resolution is linked to the pattern of injury or other factors causing a predominantly parasympathetic response following non-haemorrhagic trauma. CONCLUSION: The pattern of injury, patient demographic and speed of onset / resolution associated with the non-haemorrhagic vagal response to trauma may is heterogenous. It is therefore challenging to clinically distinguish between the hypotensive bradycardia due to hypovolaemia secondary to haemorrhage, or a parasympathetic response to trauma in the absence of bleeding.

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OBJECTIVE: Amount of seizure-free days is a critical determinant of quality of life (QoL) in patients with drug-resistant epilepsy (DRE). The fractions of patients experiencing prolonged periods of seizure freedom with adjunctive vagus nerve stimulation (VNS) have yet to be assessed on a large scale. METHODS: Retrospective analysis of patients in the Japanese VNS prospective observational registry who experienced at least 1 year of seizure freedom from all seizures, focal seizures, or tonic-clonic seizures (TCS), as well as patient-reported change in QoL in these groups. RESULTS: The study included 362 patients with DRE, 147 were female (40.6%), and the median age at VNS implant was 23.0 years (range: 1.0-73.0). A total of 225 patients reported focal seizures and 184 patients reported TCS. After 36 months of adjunctive VNS, the cumulative proportion of patients experiencing at least 1 year of complete seizure freedom was 11% (38/356) with an average duration of seizure freedom of 19.4 months. In patients with focal seizures, 25% (n = 57/225) experienced at least 1 year of freedom from focal seizures with an average duration of 24.8 months. Higher cumulative rates of freedom from TCS were observed: 55% (n = 101/184) experienced at least 1 year without TCS with an average duration of TCS-free periods of 28.9 months. 82.1% of patients with 12-month complete seizure freedom reported markedly improved or improved QoL compared with 51.9% of patients who were not seizure-free. QoL changes in patients with 12-month seizure freedom from TCS and focal seizures were similar: 61.8% and 63% of respective patients reported either markedly improved or improved QoL at 36 months. SIGNIFICANCE: Complete seizure freedom is rare in patients treated with VNS; however, this analysis found approximately half of patients who experienced TCS prior to VNS experienced prolonged periods of freedom from TCS with adjunctive VNS. PLAIN LANGUAGE SUMMARY: We studied patients in Japan with epilepsy that is difficult to treat. To understand if adding vagus nerve stimulation (VNS) helps such patients, we looked at which patients stopped having all seizures or stopped having a specific seizure type (such as tonic-clonic seizures or focal seizures), and how long these periods lasted. With VNS treatment, about 2 out of 4 patients with tonic-clonic seizures and 1 out of 4 patients with focal seizures had more time without these seizure types. Without seizures, patients felt better about their daily lives. Even patients who still had seizures felt better about their daily lives after 3 years of VNS treatment. TRIAL REGISTRATION: The clinical trial registry number is UMIN000014728.

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INTRODUCTION: Conditioned pain modulation (CPM) is a quantitative estimation of the capacity for endogenous pain modulation. Reduced CPM enables chronic painful event development or exacerbates pre-existing pain symptoms. Emerging reports indicate that patients with trigeminal neuralgia (TN) have dysregulated endogenous pain modulation. Transauricular vagus nerve stimulation (taVNS) is known to alleviate both acute and chronic pain symptoms. Its role in modulation or management of TN remains unknown. Here, we evaluated the taVNS efficacy in modulating CPM among TN patients. Conclusions from this investigation may facilitate establishment of novel non-invasive adjunctive approaches to treating TN patients. METHODS: All research work was conducted at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital). In all, we recruited 62 study participants, 31 TN patients and 31 healthy volunteers, for a 2-day experimental test. At the beginning of the experiment (Day 1), all subjects received 30 min of active taVNS. On Day 2, they received sham taVNS with the same duration and intensity. Meanwhile, technicians documented participant pressure pain thresholds (PPT) and CPM values at baseline, and at 15 and 30 min post-active or sham taVNS. RESULTS: A 30-min active taVNS exposure substantially elevated the PPT and CPM effect (P < 0.05) among TN patients, and we also observed a notable rise in the PPT and CPM effect (P < 0.05) among healthy controls. Additionally, there were no serious adverse events from the administered treatment. CONCLUSION: Exposure to 30 min of active taVNS strongly augmented the CPM effect and elevated the PPT among TN patients and healthy controls. These effects were not observed with sham stimulation. Despite the limitations inherent to survey studies, such as duration and compliance biases, we consider that taVNS is a promising, safe, and cost-effective therapy. In future investigations, we recommend assessment of long-term taVNS application and its effects on CPM and clinical pain. TRIAL REGISTRATION: ChiCTR2300078673 ( www.Chictr.org.cn ).

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Metabolic syndrome (MetS) induces a systemic inflammatory state which can lead to cardiomyopathy, manifesting clinically as heart failure (HF) with preserved ejection fraction (HFpEF). MetS components are intricately linked to the pathophysiologic processes of myocardial remodeling. Increased sympathetic nervous system activity, which is noted as an upstream factor of MetS, has been linked to adverse myocardial structural changes. Since renal denervation and vagus nerve stimulation have a sympathoinhibitory effect, attention has been paid to the cardioprotective effects of autonomic neuromodulation. In this review, the pathophysiology underlying the relationship between MetS and HF is elucidated, and the evidence regarding autonomic neuromodulation in HFpEF is summarized.

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How the body interacts with the brain to perform vital life functions, such as feeding, is a fundamental issue in physiology and neuroscience. Here, we use a whole-animal scanning transmission electron microscopy volume of Drosophila to map the neuronal circuits that connect the entire enteric nervous system to the brain via the insect vagus nerve at synaptic resolution. We identify a gut-brain feedback loop in which Piezo-expressing mechanosensory neurons in the esophagus convey food passage information to a cluster of six serotonergic neurons in the brain. Together with information on food value, these central serotonergic neurons enhance the activity of serotonin receptor 7-expressing motor neurons that drive swallowing. This elemental circuit architecture includes an axo-axonic synaptic connection from the glutamatergic motor neurons innervating the esophageal muscles onto the mechanosensory neurons that signal to the serotonergic neurons. Our analysis elucidates a neuromodulatory sensory-motor system in which ongoing motor activity is strengthened through serotonin upon completion of a biologically meaningful action, and it may represent an ancient form of motor learning.

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The research in neuroimmunomodulation aims to shed light on the complex relationships that exist between the immune and neurological systems and how they affect the human body. This multidisciplinary field focuses on the way immune responses are influenced by brain activity and how neural function is impacted by immunological signaling. This provides important insights into a range of medical disorders. Targeting both brain and immunological pathways, neuroimmunomodulatory approaches are used in clinical pain management to address chronic pain. Pharmacological therapies aim to modulate neuroimmune interactions and reduce inflammation. Furthermore, bioelectronic techniques like vagus nerve stimulation offer non-invasive control of these systems, while neuromodulation techniques like transcranial magnetic stimulation modify immunological and neuronal responses to reduce pain. Within the context of aging, neuroimmunomodulation analyzes the ways in which immunological and neurological alterations brought on by aging contribute to cognitive decline and neurodegenerative illnesses. Restoring neuroimmune homeostasis through strategies shows promise in reducing age-related cognitive decline. Research into mood disorders focuses on how immunological dysregulation relates to illnesses including anxiety and depression. Immune system fluctuations are increasingly recognized for their impact on brain function, leading to novel treatments that target these interactions. This review emphasizes how interdisciplinary cooperation and continuous research are necessary to better understand the complex relationship between the neurological and immune systems.

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The identification of acute cardioprotective strategies against myocardial ischemia/reperfusion (I/R) injury that can be applied in the catheterization room is currently an unmet clinical need and several interventions evaluated in the past at the pre-clinical level have failed in translation. Autonomic imbalance, sustained by an abnormal afferent signalling, is a key component of I/R injury. Accordingly, there is a strong rationale for neuromodulation strategies, aimed at reducing sympathetic activity and/or increasing vagal tone, in this setting. In this review we focus on cervical vagal nerve stimulation (cVNS) and on transcutaneous auricular vagus nerve stimulation (taVNS); the latest has the potential to overcome several of the issues of invasive cVNS, including the possibility of being used in an acute setting, while retaining its beneficial effects. First, we discuss the pathophysiology of I/R injury, that is mostly a consequence of the overproduction of reactive oxygen species. Second, we describe the functional anatomy of the parasympathetic branch of the autonomic nervous system and the most relevant principles of bioelectronic medicine applied to electrical vagal modulation, with a particular focus on taVNS. Then, we provide a detailed and comprehensive summary of the most relevant pre-clinical studies of invasive and non-invasive VNS that support its strong cardioprotective effect whenever there is an acute or chronic cardiac injury and specifically in the setting of myocardial I/R injury. The potential benefit in the emerging field of post cardiac arrest syndrome (PCAS) is also mentioned. Indeed, electrical cVNS has a strong anti-adrenergic, anti-inflammatory, antioxidants, anti-apoptotic and pro-angiogenic effect; most of the involved molecular pathways were already directly confirmed to take place at the cardiac level for taVNS. Pre-clinical data clearly show that the sooner VNS is applied, the better the outcome, with the possibility of a marked infarct size reduction and almost complete left ventricular reverse remodelling when VNS is applied immediately before and during reperfusion. Finally, we describe in detail the limited but very promising clinical experience of taVNS in I/R injury available so far.

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Chronic inflammation is associated with diabetes and contributes to the development and progression of micro- and macrovascular complications. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to reduce levels of circulating inflammatory cytokines in non-diabetics by activating the cholinergic anti-inflammatory pathway. We investigated the anti-inflammatory potential of tVNS as a secondary endpoint of a randomized controlled trial in people with diabetes (NCT04143269). 131 people with diabetes (type 1: n = 63; type 2: n = 68), gastrointestinal symptoms and various degrees of autonomic neuropathy were included and randomly assigned to self-administer active (n = 63) or sham (n = 68) tVNS over two successive study periods: (1) Seven days with four daily administrations and, (2) 56 days with two daily administrations. Levels of systemic inflammatory cytokines (IL-6, IL-8, IL-10, TNF-α, IFN-γ) were quantified from blood samples by multiplex technology. Information regarding age, sex, diabetes type, and the presence of cardiac autonomic neuropathy (CAN) was included in the analysis as possible confounders. No differences in either cytokine were seen after study period 1 and 2 between active and sham tVNS (all p-values > 0.08). Age, sex, diabetes type, presence of CAN, and baseline levels of inflammatory cytokines were not associated with changes after treatment (all p-values > 0.07). A tendency towards slight reductions in TNF-α levels after active treatment was observed in those with no CAN compared to those with early or manifest CAN (p = 0.052). In conclusion, tVNS did not influence the level of systemic inflammation in people with diabetes.

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Paired vagus nerve stimulation (VNS) has emerged as a promising strategy to potentiate recovery after neurological injury. This approach, which combines short bursts of electrical stimulation of the vagus nerve with rehabilitation exercises, received approval from the US Food and Drug Aministration in 2021 as the first neuromodulation-based therapy for chronic stroke. Because this treatment is increasingly implemented in clinical practice, there is a need to take stock of what we know about this approach and what we have yet to learn. Here, we provide a survey on the foundational basis of VNS therapy for stroke and offer insight into the mechanisms that underlie potentiated recovery, focusing on the principles of neuromodulatory reinforcement. We discuss the current state of observations regarding synaptic reorganization in motor networks that are enhanced by VNS, and we propose other prospective loci of neuromodulation that should be evaluated in the future. Finally, we highlight the future opportunities and challenges to be faced as this approach is increasingly translated to clinical use. Collectively, a clearer understanding of the mechanistic basis of VNS therapy may reveal ways to maximize its benefits.

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BACKGROUND: The medullary nucleus of solitary tract (NTS) and its afferents of vagus nerve have long been investigated in regulation of cortical activity and sleep promotion. However, the underlying neural circuit by which the NTS regulates electroencephalogram (EEG) and sleep remain unclear. As the NTS has a strong projection to the pontine arousal site, the parabrachial nucleus (PB), we proposed the NTS via the pontine parabrachial nucleus (PB) regulates cortical activity and sleep. METHODS: We bilaterally and directly stimulated the NTS neurons by chemogenetic approach and NTS terminals in the PB by optogenetic approach and examined changes in EEG and sleep in rats. RESULTS: Opto- and chemo-stimulation of the NTS and NTS-PB pathway altered neither sleep amounts nor patterns; however, both stimulations consistently increased EEG delta (0.5-4.0 Hz) EEG power during non-rapid-eye-movement (NREM) sleep and alpha-beta (10-30 Hz) EEG power during wake and REM sleep. CONCLUSION: Our results indicate that the NTS via its projections to the PB synchronizes low frequency EEG during NREM sleep and high frequency EEG during wake and REM sleep. This pathway may serve the neural foundation for the vagus nerve stimulation (VNS) treating cortical disorders.

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Despite its efficacy in human epidermal growth factor receptor 2 positive cancer treatment, trastuzumab-induced cardiotoxicity (TIC) has become a growing concern. Due to the lack of cardiomyocyte regeneration and proliferation in adult heart, cell death significantly contributes to cardiovascular diseases. Cardiac autonomic modulation by vagus nerve stimulation (VNS) has shown cardioprotective effects in several heart disease models, while the effects of VNS and its underlying mechanisms against TIC have not been found. Forty adult male Wistar rats were divided into 5 groups: (i) control without VNS (CSham) group, (ii) trastuzumab (4 mg/kg/day, i.p.) without VNS (TSham) group, (iii) trastuzumab + VNS (TVNS) group, (iv) trastuzumab + VNS + mAChR blocker (atropine; 1 mg/kg/day, ip, TVNS + Atro) group, and (v) trastuzumab + VNS + nAChR blocker (mecamylamine; 7.5 mg/kg/day, ip, TVNS + Mec) group. Our results showed that trastuzumab induced cardiac dysfunction by increasing autonomic dysfunction, mitochondrial dysfunction/dynamics imbalance, and cardiomyocyte death including apoptosis, autophagic deficiency, pyroptosis, and ferroptosis, which were notably alleviated by VNS. However, mAChR and nAChR blockers significantly inhibited the beneficial effects of VNS on cardiac autonomic dysfunction, mitochondrial dysfunction, cardiomyocyte apoptosis, pyroptosis, and ferroptosis. Only nAChR could counteract the protective effects of VNS on cardiac mitochondrial dynamics imbalance and autophagy insufficiency. Therefore, VNS prevented TIC by rebalancing autonomic activity, ameliorating mitochondrial dysfunction and cardiomyocyte death through mAChR and nAChR activation. The current study provides a novel perspective elucidating the potential treatment of VNS, thus also offering other pharmacological therapeutic promises in TIC patients.

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