Exploring Electrical Neuromodulation as an Alternative Therapeutic Approach in Inflammatory Bowel Diseases

Medicina (Kaunas). 2024 Apr 27;60(5):729. doi: 10.3390/medicina60050729.

ABSTRACT

Background and Objectives: This review systematically evaluates the potential of electrical neuromodulation techniques-vagus nerve stimulation (VNS), sacral nerve stimulation (SNS), and tibial nerve stimulation (TNS)-as alternative treatments for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s Disease (CD). It aims to synthesize current evidence on the efficacy and safety of these modalities, addressing the significant burden of IBD on patient quality of life and the limitations of existing pharmacological therapies. Materials and Methods: We conducted a comprehensive analysis of studies from PubMed, focusing on research published between 1978 and 2024. The review included animal models and clinical trials investigating the mechanisms, effectiveness, and safety of VNS, SNS, and TNS in IBD management. Special attention was given to the modulation of inflammatory responses and its impact on gastrointestinal motility and functional gastrointestinal disorders associated with IBD. Results: Preliminary findings suggest that VNS, SNS, and TNS can significantly reduce inflammatory markers and improve symptoms in IBD patients. These techniques also show potential in treating related gastrointestinal disorders during IBD remission phases. However, the specific mechanisms underlying these benefits remain to be fully elucidated, and there is considerable variability in treatment parameters. Conclusions: Electrical neuromodulation holds promise as a novel therapeutic avenue for IBD, offering an alternative to patients who do not respond to traditional treatments or experience adverse effects. The review highlights the need for further rigorous studies to optimize stimulation parameters, understand long-term outcomes, and integrate neuromodulation effectively into IBD treatment protocols.

PMID:38792911 | DOI:10.3390/medicina60050729

The Development of a New Vagus Nerve Simulation Electroceutical to Improve the Signal Attenuation in a Living Implant Environment

Sensors (Basel). 2024 May 16;24(10):3172. doi: 10.3390/s24103172.

ABSTRACT

An electroceutical is a medical device that uses electrical signals to control biological functions. It can be inserted into the human body as an implant and has several crucial advantages over conventional medicines for certain diseases. This research develops a new vagus nerve simulation (VNS) electroceutical through an innovative approach to overcome the communication limitations of existing devices. A phased array antenna with a better communication performance was developed and applied to the electroceutical prototype. In order to effectively respond to changes in communication signals, we developed the steering algorithm and firmware, and designed the smart communication protocol that operates at a low power that is safe for the patients. This protocol is intended to improve a communication sensitivity related to the transmission and reception distance. Based on this technical approach, the heightened effectiveness and safety of the prototype have been ascertained, with the actual clinical tests using live animals. We confirmed the signal attenuation performance to be excellent, and a smooth communication was achieved even at a distance of 7 m. The prototype showed a much wider communication range than any other existing products. Through this, it is conceivable that various problems due to space constraints can be resolved, hence presenting many benefits to the patients whose last resort to the disease is the VNS electroceutical.

PMID:38794024 | DOI:10.3390/s24103172

Cholinergic Stimulation Exerts Cardioprotective Effects and Alleviates Renal Inflammatory Responses after Acute Myocardial Infarction in Spontaneous Hypertensive Rats (SHRs)

Pharmaceuticals (Basel). 2024 Apr 24;17(5):547. doi: 10.3390/ph17050547.

ABSTRACT

BACKGROUND: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs).

METHODS: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. The clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury.

RESULTS: Seven days post-surgery, the AMI + PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI + Veh group. Furthermore, there was a notable downregulation in pro-inflammatory gene expression and an upregulation in anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers, indicative of subclinical kidney injury.

CONCLUSIONS: Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.

PMID:38794117 | DOI:10.3390/ph17050547

A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis

Neuromodulation. 2024 May 25:S1094-7159(24)00065-5. doi: 10.1016/j.neurom.2024.03.002. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to conduct a systematic review and meta-analysis assessing the antiinflammatory effects of various VNS methods while exploring multiple antiinflammatory pathways.

MATERIALS AND METHODS: We included clinical trials that used electrical stimulation of the vagus nerve and assessed inflammatory markers up to October 2022. We excluded studies lacking control groups, those with combined interventions, or abstracts without full text. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews. For each inflammatory marker, a random-effects meta-analysis using the inverse variance method was performed. Methods used include transcutaneous auricular VNS (taVNS), transcutaneous cervical VNS (tcVNS), invasive cervical VNS (iVNS), and electroacupuncture VNS (eaVNS). Main reported outcomes included tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), and IL-10. Risk of bias was evaluated using the Cochrane Collaboration Tool (RoB 2.0).

RESULTS: This review included 15 studies, involving 597 patients. No statistically significant general VNS effect was observed on TNF-α, IL-6, and IL-1ß. However, CRP, IL-10, and interferon (IFN)-γ were significantly modulated by VNS across all methods. Subgroup analysis revealed specific stimulation techniques producing significant results, such as taVNS effects in IL-1ß and IL-10, and iVNS in IL-6, whereas tcVNS and eaVNS did not convey significant pooled results individually. Cumulative exposure to VNS, higher risk of bias, study design, and pulse width were identified as effect size predictors in our meta-regression models.

CONCLUSIONS: Pooling all VNS techniques indicated the ability of VNS to modulate inflammatory markers such as CRP, IL-10, and IFN-γ. Individually, methods such as taVNS were effective in modulating IL-1ß and IL-10, whereas iVNS modulated IL-6. However, different VNS techniques should be separately analyzed in larger, homogeneous, and powerful studies to achieve a clearer and more consistent understanding of the effect of each VNS method on the inflammatory system.

PMID:38795094 | DOI:10.1016/j.neurom.2024.03.002

Retention rate of vagus nerve stimulation for the treatment of drug-resistant epilepsy: A single-centre, retrospective study

Epilepsy Res. 2024 May 21;203:107383. doi: 10.1016/j.eplepsyres.2024.107383. Online ahead of print.

ABSTRACT

The aim of this single-centre, retrospective, observational study was to evaluate long-term effectiveness of vagus nerve stimulation (VNS) in drug-resistant epilepsy (DRE) by using retention rate as a surrogate measure for seizure reduction. We included all patients with DRE, treated at the adult neurology department of the University Hospitals Leuven and who started VNS therapy from January 1, 1994, until May 1, 2021, with follow-up data cutoff on January 1, 2023. Retention rate of VNS was defined as the percentage of patients who maintain VNS at established time points. We estimated cumulative retention rate and battery replacement rate and correlated these with seizure reduction, using Kaplan-Meier analysis. Statistical analysis of potential predictors of VNS outcome (age, sex and epilepsy duration at implantation) was performed using mono- and multivariate analyses. VNS was started in 110 patients with DRE, with a mean follow-up of 8.7 years (SD 6.5). VNS was discontinued in 55 patients (50%), with ineffectiveness as the main reason for discontinuation (98%). The battery was replaced at least once in 42 patients (38%). Estimated retention rates were 70%, 52%, 45% and 33% after 5, 10, 15 and 20 years, respectively. Estimated first battery replacement rates were 16%, 42% and 47% after 5, 10 and 15 years, respectively. Both estimates showed a statistically significant correlation with seizure reduction. No independent predictors of long-term outcome of VNS were found. This is the first long-term study using retention rate of VNS to assess effectiveness. VNS is a well-tolerated therapy, but retention rates decline with long follow-up.

PMID:38795656 | DOI:10.1016/j.eplepsyres.2024.107383

Speed of heart rate changes during postural provocations in children and adolescents

Sci Rep. 2024 May 24;14(1):11938. doi: 10.1038/s41598-024-62000-7.

ABSTRACT

Heart rate is under constant autonomic influence but the development of the influence in children is not fully understood. Continuous electrocardiograms were obtained in 1045 healthy school-age children (550 females) during postural provocations with body position changes between supine, sitting, standing, supine, standing, sitting and supine (in this order), 10 min in each position with position changes within 20 s. Heart rate was measured in each position and speed of heart rate changes between positions were assessed by regressions of rates versus timing of individual cardiac cycles. Supine heart rate was gradually decreasing with age: 82.32 ± 9.92, 74.33 ± 9.79, 67.43 ± 9.45 beats per minute (bpm) in tertile age groups < 11, 11-15, > 15 years, respectively (p < 0.0001), with no significant sex difference. Averaged speed of heart rate changes differed little between sexes and age groups but was significantly faster during rate deceleration than acceleration (e.g., supine ↔ standing: 2.99 ± 1.02 vs. 2.57 ± 0.68 bpm/s, p < 0.0001). The study suggests that in children, vagal heart rate control does not noticeably change between ages of approximately 6-19 years. The gradual resting heart rate decrease during childhood and adolescence is likely caused by lowering of cardiac sympathetic influence from sympathetic overdrive in small children to adult-like sympatho-vagal balance in older adolescents.

PMID:38789480 | DOI:10.1038/s41598-024-62000-7

Postinspiratory and preBötzinger complexes contribute to respiratory-sympathetic coupling in mice before and after chronic intermittent hypoxia

Front Neurosci. 2024 May 6;18:1386737. doi: 10.3389/fnins.2024.1386737. eCollection 2024.

ABSTRACT

The sympathetic nervous system modulates arterial blood pressure. Individuals with obstructive sleep apnea (OSA) experience numerous nightly hypoxic episodes and exhibit elevated sympathetic activity to the cardiovascular system leading to hypertension. This suggests that OSA disrupts normal respiratory-sympathetic coupling. This study investigates the role of the postinspiratory complex (PiCo) and preBötzinger complex (preBötC) in respiratory-sympathetic coupling under control conditions and following exposure to chronic intermittent hypoxia (CIH) for 21 days (5% O2-80 bouts/day). The surface of the ventral brainstem was exposed in urethane (1.5 g/kg) anesthetized, spontaneously breathing adult mice. Cholinergic (ChAT), glutamatergic (Vglut2), and neurons that co-express ChAT and Vglut2 at PiCo, as well as Dbx1 and Vglut2 neurons at preBötC, were optogenetically stimulated while recording activity from the diaphragm (DIA), vagus nerve (cVN), and cervical sympathetic nerve (cSN). Following CIH exposure, baseline cSN activity increased, breathing frequency increased, and expiratory time decreased. In control mice, stimulating PiCo specific cholinergic-glutamatergic neurons caused a sympathetic burst during all phases of the respiratory cycle, whereas optogenetic activation of cholinergic-glutamatergic PiCo neurons in CIH mice increased sympathetic activity only during postinspiration and late expiration. Stimulation of glutamatergic PiCo neurons increased cSN activity during the postinspiratory phase in control and CIH mice. Optogenetic stimulation of ChAT containing neurons in the PiCo area did not affect sympathetic activity under control or CIH conditions. Stimulating Dbx1 or Vglut2 neurons in preBötC evoked an inspiration and a concomitant cSN burst under control and CIH conditions. Taken together, these results suggest that PiCo and preBötC contribute to respiratory-sympathetic coupling, which is altered by CIH, and may contribute to the hypertension observed in patients with OSA.

PMID:38774786 | PMC:PMC11107097 | DOI:10.3389/fnins.2024.1386737

Virtual reality-assessment of social interactions and prognosis in depression

J Affect Disord. 2024 May 21;359:234-240. doi: 10.1016/j.jad.2024.05.098. Online ahead of print.

ABSTRACT

BACKGROUND: Freud proposed that excessive self-blame-related motivations such as self-punishing tendencies play a key role in depression. Most of the supporting evidence, however, is based on cross-sectional studies and questionnaire measures.

METHODS: In this pre-registered (NCT04593537) study, we used a novel Virtual Reality (VR) task to determine whether maladaptive self-blame-related action tendencies prospectively identify a subgroup of depression with poor prognosis when treated as usual over four months in primary care. Ninety-eight patients with depression (Patient Health Questionnaire-9 ≥ 15), screening negatively for bipolar and alcohol/substance use disorders, completed the VR-task at baseline (n = 93 completed follow-up).

RESULTS: Our pre-registered statistical/machine learning model prospectively predicted a cross-validated 19 % of variance in depressive symptoms. Contrary to our specific predictions, and in accordance with Freud’s observations, feeling like punishing oneself emerged as prognostically relevant rather than feeling like hiding or creating a distance from oneself. Using a principal components analysis of all pre-registered continuous measures, a factor most strongly loading on feeling like punishing oneself for other people’s wrongdoings (β = 0.23, p = 0.01), a baseline symptom factor (β = 0.30, p = 0.006) and Maudsley Staging Method treatment-resistance scores (β = 0.28, p = 0.009) at baseline predicted higher depressive symptoms after four months.

LIMITATIONS: Patients were not assessed with a diagnostic interview.

CONCLUSIONS: Independently and apart from known clinical variables, feeling like punishing oneself emerged as a distinctly relevant prognostic factor and should therefore be assessed and tackled in personalised care pathways for difficult-to-treat depression.

PMID:38777276 | DOI:10.1016/j.jad.2024.05.098

The protective role of vagus nerve stimulation in ischemia-reperfusion injury

Heliyon. 2024 May 9;10(10):e30952. doi: 10.1016/j.heliyon.2024.e30952. eCollection 2024 May 30.

ABSTRACT

Ischemia-reperfusion injury (IRI) encompasses the damage resulting from the restoration of blood supply following tissue ischemia. This phenomenon commonly occurs in clinical scenarios such as hemorrhagic shock, severe trauma, organ transplantation, and thrombolytic therapy. Despite its prevalence, existing treatments exhibit limited efficacy against IRI. Vagus nerve stimulation (VNS) is a widely utilized technique for modulating the autonomic nervous system. Numerous studies have demonstrated that VNS significantly reduces IRI in various organs, including the heart, brain, and liver. This article reviews the pathological processes during IRI and summarizes the role and possible mechanisms of VNS in IRI of different organs. Furthermore, this review addresses the current challenges of VNS clinical applications, providing a novel perspective on IRI treatment.

PMID:38770302 | PMC:PMC11103530 | DOI:10.1016/j.heliyon.2024.e30952

Efficacy and safety of transcutaneous auricular vagus nerve stimulation (ta-VNS) in the treatment of tinnitus: protocol for an updated systematic review and meta-analysis

BMJ Open. 2024 May 21;14(5):e082906. doi: 10.1136/bmjopen-2023-082906.

ABSTRACT

INTRODUCTION: With an increasing incidence and significant effects on patients, tinnitus has become a major disease burden. There is a dearth of therapies with established efficacy for tinnitus. Transcutaneous auricular vagus nerve stimulation (ta-VNS) is being investigated as a potential therapy for tinnitus, but the current body of evidence remains inconclusive due to conflicting results across different studies. As a result, this protocol aims to synthesise and update the evidence to clarify whether ta-VNS is effective and safe for alleviating tinnitus.

METHODS AND ANALYSIS: To identify relevant randomised controlled trials (RCTs), seven representative bibliographical databases will be searched from their inception to December 2023: PubMed, Embase (via OVID), Cochrane Library, Chinese National Knowledge Infrastructure, Wangfang Database, Chinese BioMedical Literature Database, and Chongqing VIP Chinese Science and Technology Periodical Database. Publications in English or Chinese will be considered for inclusion. RCTs comparing ta-VNS with active treatments, no intervention, waitlist control or sham ta-VNS in adult patients with subjective tinnitus will be included. Studies on objective tinnitus will be excluded. Primary outcome is tinnitus symptom severity measured by validated scales. With all eligible trials included, when applicable, quantitative analysis via meta-analyses will be performed using RevMan V.5.4.1 software. Otherwise, a qualitative analysis will be conducted. The methodological quality of the included RCTs will be assessed using the Risk of Bias 2.0 tool. Sensitivity analyses, subgroup analysis and publication bias evaluation will also be performed. The Grading of Recommendations, Assessment, Development, and Evaluation approach will be used to grade the certainty of the evidence.

ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review, as no primary data will be collected. The results will be reported and disseminated through publication in a peer-reviewed journal.

PROSPERO REGISTRATION NUMBER: CRD42022351917.

PMID:38772894 | PMC:PMC11110564 | DOI:10.1136/bmjopen-2023-082906