Transcutaneous Auricular Vagus Nerve Stimulation Ameliorates Preeclampsia-Induced Apoptosis of Placental Trophoblastic Cells Via Inhibiting the Mitochondrial Unfolded Protein Response

Neurosci Bull. 2024 Jun 14. doi: 10.1007/s12264-024-01244-9. Online ahead of print.

ABSTRACT

Preeclampsia is a serious obstetric complication. Currently, there is a lack of effective preventive approaches for this disease. Recent studies have identified transcutaneous auricular vagus nerve stimulation (taVNS) as a potential novel non-pharmaceutical therapeutic modality for preeclampsia. In this study, we investigated whether taVNS inhibits apoptosis of placental trophoblastic cells through ROS-induced UPRmt. Our results showed that taVNS promoted the release of acetylcholine (ACh). ACh decreased the expression of UPRmt by inhibiting the formation of mitochondrial ROS (mtROS), presumably through M3AChR. This reduced the release of pro-apoptotic proteins (cleaved caspase-3, NF-κB-p65, and cytochrome C) and helped preserve the morphological and functional integrity of mitochondria, thus reducing the apoptosis of placental trophoblasts, improving placental function, and relieving preeclampsia. Our study unravels the potential pathophysiological mechanism of preeclampsia. In-depth characterization of the UPRmt is essential for developing more effective therapeutic strategies for preeclampsia targeting mitochondrial function.

PMID:38874677 | DOI:10.1007/s12264-024-01244-9

Enteric neuropathy and the vagus nerve: Therapeutic implications

Neurogastroenterol Motil. 2024 Jun 14:e14842. doi: 10.1111/nmo.14842. Online ahead of print.

ABSTRACT

Enteric neuropathies are characterized by abnormalities of gut innervation, which includes the enteric nervous system, inducing severe gut dysmotility among other dysfunctions. Most of the gastrointestinal tract is innervated by the vagus nerve, the efferent branches of which have close interconnections with the enteric nervous system and whose afferents are distributed throughout the different layers of the digestive wall. The vagus nerve is a key element of the autonomic nervous system, involved in the stress response, at the interface of the microbiota-gut-brain axis, has anti-inflammatory and prokinetic properties, modulates intestinal permeability, and has a significant capacity of plasticity and regeneration. Targeting these properties of the vagus nerve, with vagus nerve stimulation (or non-stimulation/ pharmacological methods), could be of interest in the therapeutic management of enteric neuropathies.

PMID:38873822 | DOI:10.1111/nmo.14842

Neurorehabilitation with vagus nerve stimulation: a systematic review

Front Neurol. 2024 May 30;15:1390217. doi: 10.3389/fneur.2024.1390217. eCollection 2024.

ABSTRACT

OBJECTIVE: To systematically review vagus nerve stimulation (VNS) studies to present data on the safety and efficacy on motor recovery following stroke, traumatic brain injury (TBI), and spinal cord injury (SCI).

METHODS: Data sources: PubMed, EMBASE, SCOPUS, and Cochrane.

STUDY SELECTION: Clinical trials of VNS in animal models and humans with TBI and SCI were included to evaluate the effects of pairing VNS with rehabilitation therapy on motor recovery.

DATA EXTRACTION: Two reviewers independently assessed articles according to the evaluation criteria and extracted relevant data electronically.

DATA SYNTHESIS: Twenty-nine studies were included; 11 were animal models of stroke, TBI, and SCI, and eight involved humans with stroke. While there was heterogeneity in methods of delivering VNS with respect to rehabilitation therapy in animal studies and human non-invasive studies, a similar methodology was used in all human-invasive VNS studies. In animal studies, pairing VNS with rehabilitation therapy consistently improved motor outcomes compared to controls. Except for one study, all human invasive and non-invasive studies with controls demonstrated a trend toward improvement in motor outcomes compared to sham controls post-intervention. However, compared to non-invasive, invasive VNS, studies reported severe adverse events such as vocal cord palsy, dysphagia, surgical site infection, and hoarseness of voice, which were found to be related to surgery.

CONCLUSION: Our review suggests that VNS (non-invasive or invasive) paired with rehabilitation can improve motor outcomes after stroke in humans. Hence, VNS human studies are needed in these populations (referring to SCI and TBI?) or just SCI. There are risks related to device implantation to deliver invasive VNS compared to non-invasive VNS. Future human comparison studies are required to study and quantify the efficacy vs. risks of paired VNS delivered via different methods with rehabilitation, which would allow patients to make an informed decision.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=330653.

PMID:38872818 | PMC:PMC11169586 | DOI:10.3389/fneur.2024.1390217

State- and frequency-dependence in autonomic rebalance mediated by intradermal auricular electroacupuncture stimulation

Front Neurosci. 2024 May 23;18:1367266. doi: 10.3389/fnins.2024.1367266. eCollection 2024.

ABSTRACT

BACKGROUND: Vagus nerve stimulation (VNS) improves diseases such as refractory epilepsy and treatment-resistant depression, likely by rebalancing the autonomic nervous system (ANS). Intradermal auricular electro-acupuncture stimulation (iaES) produces similar effects. The aim of this study was to determine the effects of different iaES frequencies on the parasympathetic and sympathetic divisions in different states of ANS imbalance.

METHODS: We measured heart rate variability (HRV) and heart rate (HR) of non-modeled (normal) rats with the treatment of various frequencies to determine the optimal iaES frequency. The optimized iaES frequency was then applied to ANS imbalance model rats to elucidate its effects.

RESULTS: 30 Hz and 100 Hz iaES clearly affected HRV and HR in normal rats. 30 Hz iaES increased HRV, and decreased HR. 100 Hz iaES decreased HRV, and increased HR. In sympathetic excited state rats, 30 Hz iaES increased HRV. 100 Hz iaES increased HRV, and decreased HR. In parasympathetic excited state rats, 30 Hz and 100 Hz iaES decreased HRV. In sympathetic inhibited state rats, 30 Hz iaES decreased HRV, while 100 Hz iaES decreased HR. In parasympathetic inhibited rats, 30 Hz iaES decreased HR and 100 Hz iaES increased HRV.

CONCLUSION: 30 Hz and 100 Hz iaES contribute to ANS rebalance by increasing vagal and sympathetic activity with different amplifications. The 30 Hz iaES exhibited positive effects in all the imbalanced states. 100 Hz iaES suppressed the sympathetic arm in sympathetic excitation and sympathetic/parasympathetic inhibition and suppressed the vagal arm and promoted the sympathetic arm in parasympathetic excitation and normal states.

PMID:38846714 | PMC:PMC11153749 | DOI:10.3389/fnins.2024.1367266

The dual effect of vagus nerve stimulation in pediatric patients with drug-resistant epilepsy: Is there more than seizure control?

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

Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds

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