Front Neurosci. 2024 Nov 5;18:1471387. doi: 10.3389/fnins.2024.1471387. eCollection 2024.

ABSTRACT

BACKGROUND: Melatonin (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.

METHODS: Adult 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.

RESULTS: Compared 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.

CONCLUSION: The glucose reduction effect of taVNS may be related to regulating MLT levels and expressing intestinal MRs.

PMID:39564526 | PMC:PMC11573758 | DOI:10.3389/fnins.2024.1471387

Sci Transl Med. 2024 Nov 20;16(774):eadl2184. doi: 10.1126/scitranslmed.adl2184. Epub 2024 Nov 20.

ABSTRACT

Inflammatory bowel diseases (IBDs) are chronic debilitating conditions without cure, the etiologies of which are unknown, that shorten the lifespans of 7 million patients worldwide by nearly 10%. Here, we found that decreased autonomic parasympathetic tone resulted in increased IBD susceptibility and mortality in mouse models of disease. Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10/α7 nicotinic cholinergic vagal pathway. Colonic biopsies from patients with IBDs and mouse models showed an increase in small ubiquitin-like modifier (SUMO)2 and SUMO3 during active disease. In global genetic knockout mouse models, the deletion of Sumo3 protected against development of colitis and delayed onset of disease, whereas deletion of Sumo1 halted the progression of colitis. Bone marrow transplants from Sumo1-knockout (KO) but not Sumo3-KO mice into wild-type mice conferred protection against development of colitis. Electric stimulation of the cervical vagus nerve before the induction of colitis inhibited SUMOylation and delayed the onset of colitis in Sumo1-KO mice and resulted in milder symptoms in Sumo3-KO mice. Treatment with TAK-981, a first-in-class inhibitor of the SUMO-activating enzyme, ameliorated disease in three murine models of IBD and reduced intestinal permeability and bacterial translocation in a severe model of the disease, suggesting the potential to reduce progression to sepsis. These results reveal a pathway of vagal neuromodulation that reprograms endogenous stress-adaptive responses through inhibition of SUMOylation and suggest SUMOylation as a therapeutic target for IBD.

PMID:39565873 | DOI:10.1126/scitranslmed.adl2184

Brain Stimul. 2024 Nov 18;17(6):1283-1285. doi: 10.1016/j.brs.2024.11.008. Online ahead of print.

NO ABSTRACT

PMID:39566596 | DOI:10.1016/j.brs.2024.11.008

Brain Behav Immun. 2024 Nov 19;124:28-39. doi: 10.1016/j.bbi.2024.11.023. Online ahead of print.

ABSTRACT

The vagus nerve is a crucial component of the parasympathetic nervous system, facilitating communication between the brain and various organs, including the ears, heart, lungs, pancreas, spleen, and gastrointestinal tract. The caudal nucleus of the solitary tract in the brainstem is the initial site regulated by the vagus nerve in brain-body communication, including the interactions with immune system. Increasing evidence suggests that the gut-brain axis, via the vagus nerve, may play a role in the development and progression of psychiatric, neurologic, and inflammation-related disorders. Population-based cohort studies indicate that truncal vagotomy may reduce the risk of neurological disorders such as Parkinson’s disease and Alzheimer’s disease, underscoring the vagus nerve’s significance in these conditions. Given its role in the cholinergic anti-inflammatory pathway, α7 nicotinic acetylcholine receptors present a potential therapeutic target. Additionally, noninvasive transcutaneous auricular vagus nerve stimulation (taVNS) shows promise as a therapeutic tool for these disorders. This article provides a historical review of the vagus nerve and explores its role in brain-body communication. Finally, we discuss future directions, including the potential of noninvasive taVNS as a therapeutic approach.

PMID:39566667 | DOI:10.1016/j.bbi.2024.11.023

Methods Mol Biol. 2025;2868:285-301. doi: 10.1007/978-1-0716-4200-9_15.

ABSTRACT

An intricate relationship exists between the vagus nerve and systemic immune cell regulation, specifically during fetal development. Little is known about the connection between the vagus nerve and the brain’s regional circulatory control. In this chapter, we present a methodology for studying the impact of vagus nerve signaling on these connections in the developing fetus using the sheep model for human fetal physiology. First, we present the protocol to study the connection between the vagus nerve physiology and the regional cerebral blood flow (rCBF). Next, we detail the protocol for measuring how vagal signaling alters microglial cell plasticity in gut and brain. In previous work, our team showed that vagotomy results in amplified redistribution of rCBF toward subcortical structures in the fetal brain. Conversely, efferent VNS reduces rCBF to cortical structures while afferent VNS diminishes the rise of rCBF to subcortical structures (independent of cortical rCBF) when compared to controls in the fetal brain. Additionally, our team showed that Iba-1 expression, a marker for microglial cellular signaling activation, rises in a dose-dependent relationship with systemic inflammatory activation in the setting of vagotomy. The findings support existing preclinical and clinical evidence in adult human physiology that vagotomy is neuroprotective for neurodegenerative diseases such as Parkinson’s likely via a glial cell-mediated mechanism. Vagus nerve stimulation (VNS) has also been shown to alter rCBF patterns in adults with treatment-resistant depression, underscoring the importance of further investigation of the relationship between the vagus nerve and rCBF as early as in utero. Together, the body of evidence emphasizes that the vagal pathway is an important player in the programming of microglial cell phenotypes within the developing brain. Further study is needed to better understand the significance of these relationships for the development and treatment of early susceptibility to neuroinflammatory and neurodegenerative disorders in later life. Therefore, we present a methodology for assessing rCBF and morphometric features of microglial and macrophage cell activation to allow future teams to expand on the existing body of work and further examine these relationships at a cellular and systems’ levels.

PMID:39546236 | DOI:10.1007/978-1-0716-4200-9_15

Psychoradiology. 2024 Nov 4;4:kkae016. doi: 10.1093/psyrad/kkae016. eCollection 2024.

ABSTRACT

BACKGROUND: We reported a case of cervical invasive vagus nerve stimulation (iVNS) treatment for avoidant/restrictive food intake disorder (ARFID) in a patient with severe anxiety and depression. This patient was even given a critical illness notice during his hospitalization and all treatment efforts were failed.

OBJECTIVE: We aimed to verfiy the effectiveness of iVNS in a patient with ARFID.

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 1 to 19 July 2023), the patient’s clinical symptoms improved significantly and he rapidly gained 5 kg in weight. The brain functional characteristics of this patient tended toward those of the normal group. Functional connectivities of the medial of orbitalis prefrontal cortex returned to the normal range after iVNS.

CONCLUSION: 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.

PMID:39539529 | PMC:PMC11560375 | DOI:10.1093/psyrad/kkae016

Nat Commun. 2024 Nov 13;15(1):9824. doi: 10.1038/s41467-024-54056-w.

ABSTRACT

Gastric pain has limited treatment options and the mechanisms within the central circuitry remain largely unclear. This study investigates the central circuitry in gastric pain induced by noxious gastric distension (GD) in mice. Here, we identified that the nucleus tractus solitarius (NTS) serves as the first-level center of gastric pain, primarily via the vagus nerve. The prelimbic cortex (PL) is engaged in the perception of gastric pain. The lateral parabrachial nucleus (LPB) and the paraventricular thalamic nucleus (PVT) are crucial regions for synaptic transmission from the NTS to the PL. The glutamatergic tetra-synaptic NTS-LPB-PVT-PL circuitry is necessary and sufficient for the processing of gastric pain. Overall, our finding reveals a glutamatergic tetra-synaptic NTS-LPB-PVT-PL circuitry that transmits gastric nociceptive signaling by the vagus nerve in mice. It provides an insight into the gastric pain ascending pathway and offers potential therapeutic targets for relieving visceral pain.

PMID:39537596 | PMC:PMC11561356 | DOI:10.1038/s41467-024-54056-w

West Afr J Med. 2024 Nov 10;41(11 Suppl 1):S20-S21.

ABSTRACT

SUMMARY/INTRODUCTION: Cephalic tetanus (CT) constitutes only 1-3% of total reported tetanus cases. It is marked by flaccid paralysis of one or more cranial nerves (CN) with or without spasticity, typically following craniofacial injuries. The facial nerve is the most frequently paralyzed. Other CNs are rarely involved but mostly alongside facial nerve palsy. Broomstick injury as a portal of entry has been reported in generalized tetanus but not in CT to the best of our knowledge. Here is presented a case of CT with two peculiarities: broomstick penetrating ear trauma as a portal of entry, and an unusual onset with features of isolated glossopharyngeal and/or vagus nerve palsy.

CASE REPORT: A 30-month-old unimmunized male who one week before presentation developed sudden-onset dysphagia, drooling, nasal regurgitation, and rhinolalia. Two days later, he developed trismus and left-sided rd torticollis; on the 3 day, provoked spasms, initially of the face and neck muscles, and later including the limbs. Three weeks earlier he had accidentally injured his left ear while poking it with a broomstick. This was poorly managed at home without anti-tetanus prophylaxis. Examination revealed a conscious acutely ill child with risus sardonicus and episodic generalized spasms, more intense in the face and neck regions. Trismus/provoked spasms did not permit an objective assessment of glossopharyngeal, vagus, and hypoglossal nerves but other CNs were normal. Managed in a quiet, dark isolation room where he received IM anti-tetanus serum, staggered doses of chlorpromazine, phenobarbitone, diazepam; and metronidazole, his condition gradually improved, and was discharged after 21 days of hospitalization.

CONCLUSION: The rarity and sometimes unusual presentation of CT delays prompt diagnosis and early treatment leading to secondary generalization with its attendant poor outcomes. A careful history, examination, and heightened suspicion are needed. Furthermore, this report highlights ear poking, particularly with broomsticks, as a risk for CT and should be strongly discouraged.

PMID:39535734

JAMA Surg. 2024 Nov 13:e245077. doi: 10.1001/jamasurg.2024.5077. Online ahead of print.

ABSTRACT

IMPORTANCE: Radical gastric cancer surgery can cause functional and physiological disorders due to the resection of perigastric vagus nerves. Few studies have used intraoperative neurophysiological monitoring and indocyanine green (ICG) labeling to preserve the perigastric vagus nerve and to evaluate the corresponding effects.

OBJECTIVE: To assess the feasibility and effects of vagus nerve preservation using neurophysiologic monitoring and ICG labeling during laparoscopic distal gastrectomy in patients with early distal gastric cancer.

DESIGN, SETTING, AND PARTICIPANTS: This open-label, prospective randomized clinical trial initially enrolled 285 patients with clinical stage cT1N0M0 distal gastric cancer from May 2022 to May 2023. This trial was conducted at Qilu Hospital of Shandong University in Jinan, China, and enrolled patients aged 18 to 80 years with histologically proven gastric adenocarcinoma scheduled for distal gastrectomy. The final follow-up examination was performed May 1, 2024.

INTERVENTIONS: Eligible participants were randomly assigned 1:1 to vagus nerve preservation distal gastrectomy (VPG) or vagus nerve resection distal gastrectomy (VRG).

MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of postsurgical gastroparesis. Secondary outcomes included postoperative gallstone formation, quality of life, morbidity, mortality, overall survival, and disease-free survival up to 12 months postoperatively. All analyses were based on both intention-to-treat and per-protocol analyses.

RESULTS: Of 264 patients included in the intention-to-treat analysis, the median (IQR) patient age was 58.0 (52.0-67.0) years, and 67 patients (25.4%) were female. Both the VPG and VRG groups included 132 patients. Postoperative gastroparesis occurred in 1 patient (0.8%) in the VPG group and in 10 patients (7.6%) in the VRG group. Gallstones developed in 0 patients in the VPG group and in 9 patients (6.8%) in the VRG group. As assessed by mean (SD) score on the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, the VRG group experienced more nausea and vomiting at 6 months postsurgery (19.38 [7.62]) than the VPG group (17.15 [9.21]) (P = .03) and had significantly higher rates of persistent appetite loss, reflux symptoms, and eating difficulties at both 6 months and 12 months than the VPG group. Differences in postoperative complications and metastasis were not significant.

CONCLUSIONS AND RELEVANCE: Neurophysiologic monitoring and ICG labeling during distal laparoscopic gastrectomy for vagus nerve preservation in patients with early distal gastric cancer are safe and feasible. Preserving the perigastric vagus nerve may retain the function of the remnant stomach and improve quality of life.

TRIAL REGISTRATION: Chictr.org.cn Identifier: ChiCTR2200059489.

PMID:39535740 | PMC:PMC11561724 | DOI:10.1001/jamasurg.2024.5077

West Afr J Med. 2024 Nov 10;41(11 Suppl 1):S21.

ABSTRACT

SUMMARY/INTRODUCTION: Velopharyngeal incompetence(VPI) is the failure of closure of the velopharyngeal sphincter, which consists of the muscles of the soft palate and the superior pharyngeal constrictor, and functions to separate the nasopharynx and oropharynx during phonation and swallowing. VPI is most frequently congenital/syndromic (with structural deficit) but can be acquired. A subset of acquired VPI, occurring in structurally intact velopharynx, has been described in children, and these are isolated and acute-onset, with a substantial proportion thought to have an infectious origin. So far measles was identified to be the aetiology in one reported case. This report aims to create awareness that VPI could be a rare post-measles complication.

CASE REPORT: A two-year-old female who, two weeks after a measles episode, developed sudden-onset nasal regurgitation, rhinolalia, and dysphagia. She had never experienced these symptoms before and has not had any recent throat surgeries. The review of systems was not contributory. On examination, she was ill-looking with no dysmorphic features; was not febrile or pale, and had generalized brownish-scaly, desquamating skin lesions. Nasal regurgitation of liquids was observed when she drank. Oral/oropharyngeal examination revealed no structural defects but she had absent gag reflex with bilateral palatal paralysis (indicating Glossopharyngeal and Vagus nerve palsies). All other neurological and systemic findings were normal. Management was conservative with a Nasogastric tube for feeding. She made a complete recovery with total restoration of neurologic functions after 21 days. Six-month follow-up revealed no recurrence or signs of progression.

CONCLUSION: This report adds to the evidence that measles is one of the infectious causes of acute-onset isolated VPI. The proposed mechanisms underlying this unusual manifestation of measles are direct viral neuronal injury given its neurotropic nature; and autoimmune neuronal injury. The reason for the rarity of this post-measles complication despite the high incidence of measles remains to be elucidated.

PMID:39535764