Front Hum Neurosci. 2024 May 22;18:1373543. doi: 10.3389/fnhum.2024.1373543. eCollection 2024.

ABSTRACT

OBJECTIVE: This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds.

METHODS: We treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100 mg/kg/dose) was given by nasogastric (NG) administration every 6 h for 4 days, then combined with taVNS paired with 2 daily feeds for another 14 days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone.

RESULTS: NAC 100 mg/kg/dose every 6 h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13 ± 0.08 mM (p = 0.01, compared to baseline). Mean daily feeding volumes increased over 14 days of NAC + taVNS compared to the 14 days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake.

CONCLUSION: In IDM failing oral feeds, NAC 100 mg/kg/dose every 6 h NG for 4 days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.

PMID:38841121 | PMC:PMC11151742 | DOI:10.3389/fnhum.2024.1373543

Epilepsy Behav Rep. 2024 Feb 12;27:100653. doi: 10.1016/j.ebr.2024.100653. eCollection 2024.

ABSTRACT

This is a retrospective and comparative pilot study to investigate the role of vagus nerve stimulation (VNS) in improving cognitive functions in the pediatric age group with drug resistant epilepsy (DRE). It was conducted from January 2018 to February 2023. Children between the ages of 4 and 18 years were divided into two groups, the “VNS group” and the “best medical treatment (BMT) group”. Follow up period was 12 months. Demographic, clinical, etiological and investigational data were recorded. Cognitive assessment using the Modified Mini-Mental State Examination for children (MMSE) was recorded at baseline and 12 months later for each group. 76.4 % of patients were classified as epilepsy secondary to cerebral palsy. 75 % of patients showed ≥ 50 % seizure frequency reduction among the VNS group as compared to 12.5 % in the BMT group. None of both groups achieved seizure freedom. At 12 months, both BMT and VNS groups showed statistically significantly improved overall cognitive score from baseline records (p = 0.027) and (p = 0.012), respectively, with a significantly higher improvement in VNS group. Also, statistical sub-analysis of cognitive subscales in cerebral palsy patients in both groups was conducted and revealed a significant improvement (p = 0.02) in the VNS group. We concluded that there is a potential role of VNS in improving cognitive functions which was shown by using a cost-effective screening tool. A significant effect was observed specially in cerebral palsy patients. This is very beneficial in limited-resources countries since VNS has good safety profile, high seizure control, and added value to cognitive functions.

PMID:38841319 | PMC:PMC11150965 | DOI:10.1016/j.ebr.2024.100653

Front Physiol. 2024 May 21;15:1379936. doi: 10.3389/fphys.2024.1379936. eCollection 2024.

ABSTRACT

INTRODUCTION: The influence of vagus nerve stimulation (VNS) parameters on provoked cardiac effects in different levels of cardiac innervation is not well understood yet. This study examines the effects of VNS on heart rate (HR) modulation across a spectrum of cardiac innervation states, providing data for the potential optimization of VNS in cardiac therapies.

MATERIALS AND METHODS: Utilizing previously published data from VNS experiments on six sheep with intact innervation, and data of additional experiments in five rabbits post bilateral rostral vagotomy, and four isolated rabbit hearts with additionally removed sympathetic influences, the study explored the impact of diverse VNS parameters on HR.

RESULTS: Significant differences in physiological threshold charges were identified across groups: 0.09 ± 0.06 μC for intact, 0.20 ± 0.04 μC for vagotomized, and 9.00 ± 0.75 μC for isolated hearts. Charge was a key determinant of HR reduction across all innervation states, with diminishing correlations from intact (r = 0.7) to isolated hearts (r = 0.44). An inverse relationship was observed for the number of pulses, with its influence growing in conditions of reduced innervation (intact r = 0.11, isolated r = 0.37). Frequency and stimulation delay showed minimal correlations (r < 0.17) in all conditions.

CONCLUSION: Our study highlights for the first time that VNS parameters, including stimulation intensity, pulse width, and pulse number, crucially modulate heart rate across different cardiac innervation states. Intensity and pulse width significantly influence heart rate in innervated states, while pulse number is key in denervated states. Frequency and delay have less impact impact across all innervation states. These findings suggest the importance of customizing VNS therapy based on innervation status, offering insights for optimizing cardiac neuromodulation.

PMID:38835728 | PMC:PMC11148559 | DOI:10.3389/fphys.2024.1379936

Neurorehabil Neural Repair. 2024 Jun 5:15459683241258769. doi: 10.1177/15459683241258769. Online ahead of print.

ABSTRACT

BACKGROUND: Vagus nerve stimulation (VNS) combined with rehabilitation is a Food and Drug Administration approved intervention for moderate to severe upper extremity deficits in chronic ischemic stroke patients. Previous studies demonstrated that VNS improves upper extremity motor impairments, using the Fugl Meyer Assessment of Upper Extremity (FMA-UE); however, delineating where these improvements occur, and the role of VNS dosage parameters were not reported.

OBJECTIVE: This study explored the relationship between dosing (time over which task repetitions were executed and number of VNS stimulations) and changes within proximal and distal components of the FMA-UE.

METHODS: Participants underwent VNS implantation, with 1 group receiving VNS paired with rehabilitation (Active VNS) and the other group receiving rehabilitation with sham stimulation (Controls). Both groups received 6 weeks of in-clinic therapy followed by a 90-day at-home, self-rehabilitation program. Participants who completed at least 12 of 18 in-clinic sessions were included in the analyses (n = l06). Pearson correlations and analysis of covariance were used to investigate the relationship between dosing and FMA-UE outcome change along with the effect of covariates including baseline severity, time since stroke, age, and paretic side.

RESULTS: Compared to Controls, active VNS favorably influenced distal function with sustained improvement after the home program. Significant improvements were observed in only distal components (FM_dist) at both post day-1 (1.80 points, 95% Cl [0.85, 2.73], P < .001) and post-day 90 (1.62 points, 95% CI [0.45, 2.80], P < .007).

CONCLUSIONS: VNS paired with rehabilitation resulted in significant improvements in wrist and hand impairment compared to Controls, despite similar in-clinic dosing across both groups.NCT03131960.

PMID:38836606 | DOI:10.1177/15459683241258769

Asian J Psychiatr. 2024 May 28;98:104079. doi: 10.1016/j.ajp.2024.104079. Online ahead of print.

ABSTRACT

BACKGROUND: In order to improve taVNS efficacy, the usage of fMRI to explore the predictive neuroimaging markers would be beneficial for screening the appropriate MDD population before treatment.

METHODS: A total of 86 MDD patients were recruited in this study, and all subjects were conducted with the clinical scales and resting-state functional magnetic resonance imaging (fMRI) scan before and after 8 weeks’ taVNS treatment. A two-stage feature selection strategy combining Machine Learning and Statistical was used to screen out the critical brain functional connections (FC) that were significantly associated with efficacy prediction, then the efficacy prediction model was constructed for taVNS treating MDD. Finally, the model was validated by separated the responding and non-responding patients.

RESULTS: This study showed that taVNS produced promising clinical efficacy in the treatment of mild and moderate MDD. Eleven FCs were selected out and were found to be associated with the cortico-striatal-pallidum-thalamic loop, the hippocampus and cerebellum and the HAMD-17 scores. The prediction model was created based on these FCs for the efficacy prediction of taVNS treatment. The R-square of the conducted regression model for predicting HAMD-17 reduction rate is 0.44, and the AUC for classifying the responding and non-responding patients is 0.856.

CONCLUSION: The study demonstrates the validity and feasibility of combining neuroimaging and machine learning techniques to predict the efficacy of taVNS on MDD, and provides an effective solution for personalized and precise treatment for MDD.

PMID:38838458 | DOI:10.1016/j.ajp.2024.104079

Am J Physiol Cell Physiol. 2024 Jun 3. doi: 10.1152/ajpcell.00246.2024. Online ahead of print.

ABSTRACT

Major depressive disorder (MDD) affects millions of individuals worldwide, leading to considerable social and economic costs. Despite advancements in pharmacological treatments, achieving remission remains a key challenge, with a substantial number of patients showing resistance to existing therapies. This resistance is often associated with elevated levels of pro-inflammatory cytokines, suggesting a connection between inflammation, MDD pathophysiology, and treatment efficacy. The observation of increased immune activation in about a quarter of MDD patients resulted in the distinction of inflammatory and non-inflammatory endotypes. While anti-inflammatory treatments show promise in alleviating depression-like symptoms, responses are heterogeneous, thus highlighting the importance of identifying distinct inflammatory endotypes to tailor effective therapeutic strategies. The intestinal microbiome emerges as a crucial modulator of mental health, mediating its effects partially through different immune pathways. Microbiota-derived short-chain fatty acids (SCFAs) significantly impact innate and adaptive immune cells, regulating their differentiation, function, and cellular response. Furthermore, gut-educated immune cells reach the border regions of the central nervous system (CNS), regulating glial cell functions. While the CNS modulates immune responses via efferent parts of the vagus nerve, afferent tracts concurrently transport information on peripheral inflammation back to the brain. This bidirectional communication is particularly relevant in depression, allowing for therapeutic stimulation of the vagus nerve in the context of inflammatory depression endotypes. In this review, we explore the intricate relationship between inflammation and depression, discuss how inflammatory signals are translated into depressive-like symptoms, and highlight immune-modulating therapeutic avenues.

PMID:38826138 | DOI:10.1152/ajpcell.00246.2024

J Neurosci. 2024 Jun 3:e1441232024. doi: 10.1523/JNEUROSCI.1441-23.2024. Online ahead of print.

ABSTRACT

The vagal ganglia, comprised of the superior (jugular) and inferior (nodose) ganglia of the vagus nerve, receive somatosensory information from the head and neck, or viscerosensory information from the inner organs, respectively. Developmentally, the cranial neural crest gives rise to all vagal glial cells and to neurons of the jugular ganglia, while the epibranchial placode gives rise to neurons of the nodose ganglia. Crest-derived nodose glial progenitors can additionally generate autonomic neurons in the peripheral nervous system, but how these progenitors generate neurons is unknown. Here, we found that some Sox10+ neural crest-derived cells in, and surrounding, the nodose ganglion transiently expressed Phox2b, a master regulator of autonomic nervous system development, during early embryonic life. Our genetic lineage tracing analysis in mice of either sex revealed that despite their common developmental origin and extreme spatial proximity a substantial proportion of glial cells in the nodose, but not in the neighboring jugular ganglia, have a history of Phox2b expression. We used single cell RNA-sequencing (scRNA-seq) to demonstrate that these progenitors give rise to all major glial subtypes in the nodose ganglia, including Schwann cells, satellite glia and glial precursors, and mapped their spatial distribution by in situ hybridization. Lastly, integration analysis revealed transcriptomic similarities between nodose and dorsal root ganglia glial subtypes, and revealed immature nodose glial subtypes. Our work demonstrates that these crest-derived nodose glial progenitors transiently express Phox2b, give rise to the entire complement of nodose glial cells and display a transcriptional program that may underlie their bipotent nature.Significance statement The nodose ganglia contain sensory neurons that innervate inner organs and play key roles in homeostatic behaviors like digestion, regulation of blood pressure and heart rate, and breathing. Nodose sensory neurons are supported by nodose glial cells, which are understudied compared to their neuronal neighbors. Specifically, the genetic program governing their development is not fully understood. Here, we uncover a transcriptional program unique to nodose glial cells (transient expression of Phox2b) that resolves the 40-year-old finding that nodose glial progenitors can also give rise to autonomic neurons (whose development depends on Phox2b expression). Lastly, we leveraged single cell RNA-sequencing to identify the four major subtypes of nodose glial cells and used subtype specific marker genes to map their spatial distribution.

PMID:38830761 | DOI:10.1523/JNEUROSCI.1441-23.2024

Mol Ther. 2024 May 30:S1525-0016(24)00339-3. doi: 10.1016/j.ymthe.2024.05.037. Online ahead of print.

ABSTRACT

Vagus nerve regulates viral infection and inflammation via the alpha 7 nicotinic acetylcholine receptor (α7 nAChR); however, the role of α7 nAChR in ZIKA virus (ZIKV) infection, which can cause severe neurological diseases such as microcephaly and Guillain-Barré syndrome, remains unknown. Here, we first examined the role of α7 nAChR in ZIKV infection in vitro. A broad effect of α7 nAChR activation was identified in limiting ZIKV infection in multiple cell lines. Combined with transcriptomics analysis, we further demonstrated that α7 nAChR activation promoted autophagy and ferroptosis pathways to limit cellular ZIKV viral loads. Additionally, activation of α7 nAChR prevented ZIKV-induced p62 nucleus accumulation, which mediated an enhanced autophagy pathway. By regulating proteasome complex and an E3 ligase NEDD4, activation of α7 nAChR resulted in increased amount of cellular p62, which further enhanced ferroptosis pathway to reduce ZIKV infection. Moreover, utilizing in vivo neonatal mouse models, we showed that α7 nAChR is essential in controlling the disease severity of ZIKV infection. Taken together, our findings identify an α7 nAChR-mediated effect that critically contributes to limiting ZIKV infection, and α7 nAChR activation offers a novel strategy for combating ZIKV infection and its complications.

PMID:38822526 | DOI:10.1016/j.ymthe.2024.05.037

Ann Neurol. 2024 Jun 1. doi: 10.1002/ana.26956. Online ahead of print.

ABSTRACT

Outcomes following vagus nerve stimulation (VNS) improve over years after implantation in children with drug-resistant epilepsy. The added value of deep brain stimulation (DBS) instead of continued VNS optimization is unknown. In a prospective, non-blinded, randomized patient preference trial of 18 children (aged 8-17 years) who did not respond to VNS after at least 1 year, add-on DBS resulted in greater seizure reduction compared with an additional year of VNS optimization (51.9% vs. 12.3%, p = 0.047). Add-on DBS also resulted in less bothersome seizures (p = 0.03), but no change in quality of life. DBS may be considered earlier for childhood epilepsy after non-response to VNS. ANN NEUROL 2024.

PMID:38822686 | DOI:10.1002/ana.26956

Seizure. 2024 May 30;119:84-91. doi: 10.1016/j.seizure.2024.05.005. Online ahead of print.

ABSTRACT

BACKGROUND: Several studies have suggested that transcutaneous vagus nerve stimulation (tVNS) may be effective for the treatment of epilepsy. However, auricular acupoint therapy (including auricular acupuncture and auricular point-sticking therapy), a method of stimulating the vagus nerve, has been poorly reviewed. This systematic review is the first to categorize auricular acupoint therapy as transcutaneous auricular vagus nerve stimulation (taVNS), aiming to assess the efficacy of taVNS in patients with epilepsy (PWE), and to analyse the results of animal experiments on the antiepileptic effects of taVNS.

METHODS: We searched MEDLINE, EMBASE, Web of Science, Scopus, and various Chinese databases from their inception to June 10, 2023 and found nine clinical studies (including a total of 788 PWE) and eight preclinical studies. We performed a meta-analysis and systematic review of these articles to assess the efficacy of taVNS in PWE and the association between taVNS and electroencephalogram (EEG) changes. We also analysed the effects on epileptic behaviour, latency of the first seizure, and seizure frequency in epileptic animals. The PRISMA 2020 checklist provided by the EQUATOR Network was used in this study.

RESULTS: taVNS had a higher response rate in PWE than the control treatment (OR = 2.94, 95 % CI = 1.94 – 4.46, P < 0.05). The analysis showed that the taVNS group showed wider EEG changes than the control group (OR = 2.17, 95 % CI 1.03 to 4.58, P < 0.05). The preclinical studies analysis revealed significant differences in epileptic behaviour (SMD = -4.78, 95 % CI -5.86 to -3.71, P < 0.05) and seizure frequency (SMD = -5.06, 95 % CI -5.96 to -4.15, P < 0.05) between the taVNS and control groups. No statistical difference was found in the latency of the first seizure between the two groups (SMD =13.54; 95 % CI 7.76 to 19.33, P < 0.05).

CONCLUSION: Based on the available data, PWE may benefit from the use of taVNS. taVNS is an effective procedure for improving epileptic behaviour in animal models.

PMID:38820674 | DOI:10.1016/j.seizure.2024.05.005