Effects Of Vagus Nerve Stimulation Research Articles

Right-sided vagus nerve stimulation: Worldwide collection and perspectives.

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy (DRE) and is indicated for implantation on the left vagus nerve-only. In rare cases right-sided VNS may be the only option. With only seven published cases in the literature, data on safety and effectiveness of right-sided VNS is very limited. An anonymous 38-item questionnaire was sent to expert surgeons implanting VNS for DRE. The questions covered demographics and clinical characteristics, the reason for right-sided implantation and both neurological and surgical outcomes of right-sided VNS. The survey captured 38 cases of right-sided VNS (18 females, mean age at surgery of 28.0 ± 16.3 years). Right-sided VNS was performed because of VNS lead deficiency (n = 20), anatomical constraints (n = 8), infection of a left-sided VNS site (n = 9), and presence of a left ventricular shunt (n = 1). Thirty-two patients (84%) had a preoperative cardiac assessment. Three patients presented postoperative cardiac side-effects. Right-sided VNS was stopped at last follow-up in three patients: due to deep infection (n = 1), due to dyspnea (n = 1), and due to sleep apnea syndrome (n = 1). Twenty-one patients (55%) were responders to right-sided VNS and the mean reduction of seizure frequency under right-sided VNS was 56.2 ± 18.8%. Focusing on seizure frequency reduction between right-sided VNS and left-sided VNS: 20 patients experienced similar effectiveness, 1 experienced lesser effectiveness, and 2 patients experienced greater effectiveness with right-sided VNS. This multicenter case series significantly augments the available literature on right-sided VNS. This suggests comparable effectiveness to left-sided VNS but potentially lower tolerability. Further studies are warranted to better evaluate safety and efficacy of right-sided VNS.

Significant reduction of seizure frequency in patients with drug-resistant epilepsy by vagus nerve stimulation: Systematic review and meta-analysis.

Epilepsy is a major neurological disorder, typically managed with Anti-Seizure Medication (ASM). Nevertheless, a substantial 30 % of patients did not respond satisfactorily to ASMs, classifying their condition as Drug-Resistant Epilepsy (DRE). Vagus Nerve Stimulation (VNS) was recommended as a potential solution. To evaluate clinical efficacy of VNS on patients with DRE in reduction of seizures through a systematic review and meta-analysis using a random effects model. A systematic search was done from PubMed, ScienceDirect, Cochrane Library and Google Scholar databases on observational studies and randomized controlled trials (RCTs) for the clinical effectiveness of VNS among DRE patients. A meta-analysis was performed to obtain the pooled estimate of the clinical effectiveness of VNS in terms of seizure reduction and the odds ratio (OR) for patients achieving > 50 % seizure reduction. Heterogeneity was assessed using visual inspection of forest plots and I2 statistic. A total of 1023 articles were retrieved from the electronic search. After removing duplicates, non-relevance and non-availability of efficacy data, 28 articles were included in the final analysis. Of these, 9 are RCTs and 19 are observational studies. The pooled estimate of > 50 % seizure reduction was 0.46 (95 % CI: 0.40-0.51) and the pooled estimate of the OR comparing > 50 % vs ≤ 50 % seizure reduction was 0.76 (95 % CI: 0.44-1.29). Our meta-analysis showed that 46 % of DRE patients have experienced ≥ 50 % seizure reduction with VNS treatment. It should be considered in patients in whom ASM has failed or who continue to experience seizures after medication.

Stimulasi Nervus Vagus sebagai Terapi Adjuvan pada Anak Epilepsi Resisten Obat : Literature Review

Drug-resistant epilepsy is the failure to administer two or more anti-epileptic drugs to an epileptic child which becomes a challenge in its management. Failure of this therapy can result in a decrease in the child's quality of life, such as decreased cognitive function, personality disorders and sleep quality. This can also have a negative impact on the parents who care for them. Vagus nerve stimulation is a device attached to the child's left chest and neck that can stimulate the vagus nerve. This literature review provides a comprehensive overview of vagus nerve stimulation in the treatment of drug-resistant epilepsy, including a discussion of indications, techniques for use, and scientific evidence for the efficacy of vagus nerve stimulation. We reviewed and analyzed the current scientific evidence to assess the effectiveness of vagus nerve stimulation in the treatment of drug-resistant epilepsy.

Introducing the Index of Response to Stimulation (IRES): A Novel Metric for Assessing Vagus Nerve Stimulation Outcomes in Drug-Resistant Epilepsy.

Background and Objectives: The Index of Response to Stimulation (IRES) is a new index that we introduce in this study to grade the effectiveness of vagus nerve stimulation in the treatment of drug-resistant epilepsy. We assessed 76 patients at 6, 12, and 18 months after VNS evaluating improvement with the IRES in four key dimensions: seizure duration decrease, seizure intensity decrease, improvement in quality of life, and seizure frequency decrease. This scale goes from 0, meaning no improvement, to 8, meaning maximal improvement, making the scale a really good measure of clinical utility. Materials and Methods: This retrospective study followed 76 patients aged 20-65, assessing changes in their IRES scores after VNS therapy using the ASPIRE SR 106 device. Therapy settings were adjusted biweekly to optimize efficacy and patient tolerance. Results: There were improvements in the control of the seizures, measured in terms of increased IRES scores. Improvements were associated with quality-of-life enhancements for the patient and a lesser frequency and intensity of the seizures, testifying further to the predictive ability of the IRES toward successful outcomes. This fact reveals that epilepsy treatment must be individual, according to the profile of the patient. Conclusions: The study confirms the IRES to be a valid tool for the assessment of the impact of VNS on drug-resistant epilepsy and promotes it as an integral part of the evaluation of the patient for personalized therapy. The findings encourage the use of IRES among the elements that support patient selection and insist on its role in the advancement of precision medicine and optimization of treatment.

Effects of vagus nerve stimulation on daily function and quality of life in markedly treatment-resistant major depression: Findings from a one-year, randomized, sham-controlled trial.

Depression treatments aim to minimize symptom burden and optimize quality of life (QoL) and psychosocial function. Compare the effects of adjunctive versus sham vagus nerve stimulation (VNS) on QoL and function in markedly treatment-resistant depression (TRD). In this multicenter, double-blind, sham-controlled trial, 493 adults with TRD and ≥4 adequate but unsuccessful antidepressant treatment trials (current episode) were randomized to active (n=249) or sham (n=244) VNS (plus treatment as usual) over a 12-month observation period. Quarterly outcomes included QoL with the Q-LES-Q, Mini-Q-LES-Q, and EQ-5D-5L, and function with the WHODAS 2.0 and Work Productivity and Activity Impairment Questionnaire (WPAI) item 6. Differences between treatment groups in change in scores from baseline and percentage of time with a meaningful response in Q-LES-Q, Mini-Q-LES-Q, and WPAI item 6 scores were analyzed. Active VNS was superior to sham in mean change in scores from baseline in the Mini-Q-LES-Q (P=0.050) and WPAI item 6 (health condition's effect on regular activities [P=0.050]) used as continuous variables, with a similar trend for Q-LES-Q (P=0.061). Active VNS was superior to sham in time spent in clinically meaningful benefit (categorical analyses) using the Q-LES-Q (P=0.029), Mini-Q-LES-Q (P=0.011), and WPAI item 6 (P=0.039). The WHODAS 2.0 (P=0.304) and EQ-5D visual analog scale (P=0.125) failed to reveal between-group differences. Active VNS was superior to sham VNS in improving QoL and psychosocial function in patients with TRD. VNS has a broader therapeutic impact than symptom improvement alone in patients with marked psychosocial impairment.

Changes in Response Inhibition, Visual Anticipation and Verbal Fluency During Vagus Nerve Stimulation Therapy in Patients With Drug-Resistant Epilepsy.

The effect of vagus nerve stimulation (VNS) on cognitive domain of attention and executive functions (AEFs) has not been extensively researched. This study was set up to investigate performance variability on cognitive tests assessing AEFs in drug-resistant epilepsy (DRE) patients receiving VNS therapy during a follow-up of up to 5 years. Thirty-three DRE patients were assessed with the interference, maze, and written verbal fluency tests as a part of EpiTrack screening before and after VNS implantation through repeated follow-ups according to the clinical VNS protocol. A linear mixed-effects model was used to analyse changes in test scores. Maze performance improved significantly by an average of 0.20 s per month (95% confidence interval (CI): -0.365 to -0.041; p = 0.014). Interference performance improved by an average of 0.05 s per month (p = 0.207) and number of words increased by an average of 0.03 words per month (p = 0.079) on the verbal fluency test. On the maze test, patients with psychiatric comorbidities improved the most (0.52 s/month, p = 0.001), while on the interference test, patients with frontal lobe epilepsy (FLE), those taking 1-2 antiseizure medications (ASMs) and patients with focal to bilateral tonic-clonic seizures improved the most (0.14 s/month, p = 0.005; 0.14 s/month, p = 0.033 and 0.16 s/month, p = 0.087, respectively). For verbal fluency, no clinically meaningful improvement was noted in any of the groups. During the follow-up, maze performance markedly improved, while performance on the interference and verbal fluency tasks remained relatively stable at the group level. Accordingly, visual anticipation and planning improved during VNS therapy whereas response inhibition was unchanged at the group level despite significant enhancements in patients with FLE and those taking 1-2 ASM. Furthermore, the presence of psychiatric comorbidities correlated with even greater improvement on maze performance.

Vagus nerve stimulation in treatment-resistant depression: A one-year, randomized, sham-controlled trial.

Few treatments are available for individuals with marked treatment-resistant depression (TRD). Evaluate the safety and effectiveness of FDA-approved adjunctive vagus nerve stimulation (VNS) in patients with marked TRD. This 12-month, multicenter, double-blind, sham-controlled trial included 493 adults with marked treatment-resistant major depression who were randomized to active or no-stimulation sham VNS for 12 months. The primary outcome was percent time in response across months 3-12, with response defined as a ≥50% change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Several secondary endpoints were evaluated. Overall, 88.4% of participants completed the trial. Percent time in MADRS response did not distinguish active from sham VNS. However, ratings from on-site clinicians (Clinical Global Inventory-Impression [CGI-I]), patients (Quick Inventory of Depressive Symptomology-Self Report [QIDS-SR]), and offsite masked raters (Quick Inventory of Depressive Symptomology-Clinician [QIDS-C]) revealed antidepressant benefits significantly favoring active VNS. Active VNS demonstrated significantly more percent time in response on the CGI-I (P=0.004) and QIDS-SR (P=0.049), and significantly more percent time in partial response (PR; symptom improvement ≥30%) on the CGI-I (P<0.001) and QIDS-C (P=0.006) versus sham VNS. Active VNS exceeded sham VNS in rate of dyspnea (P=0.035), a known side effect of VNS. No new adverse events were identified. Percent time in MADRS response did not distinguish the treatment groups, but on multiple instruments time in response and PR showed a positive treatment effect. VNS was found safe and effective in participants with marked TRD.

Water-Triggered Self-Wrapping Cuff Electrodes for Nerve Stimulation, Oral Presentation

In recent years, there has been an increasing interest in implantable stimulation electrodes for supporting and restoring neural functions, with ongoing development efforts aimed at their application in various areas such as vagus nerve stimulation (VNS), spinal cord stimulation (SCS), and gastric electrical stimulation (GES). The development of flexible and thin electrodes is crucial due to the delicate and uneven surfaces of tissues within the body. This is particularly important for thin nerves, which require full coverage and secure adhesion. However, soft and thin electrodes are difficult to handle in the limited space inside the body during the operation. Currently, such electrodes can only be manually attached by skilled surgeons, and the process tends to be time-consuming. Here, we develop multi-layered flexible electrodes that self-wrap around the nerves by exploiting the difference in the compression-expansion rate of each layer upon wetting.The electrodes are based on a polyvinyl alcohol (PVA) hydrogel substrate with flexible carbon fibers sandwiched between them. The self-wrapping mechanism of the electrode is designed using two layers of hydrogel substrates with different compression-expansion rates upon wetting (Fig.1b). When a stretched hydrogel is adhered to an unstretched one, they deform due to the difference in stress. Additionally, the elasticity of the hydrogel decreases when it dries but is restored upon swelling. Drying the stretched hydrogel preserves the temporarily applied elasticity, enabling the hydrogel-based electrode to become round when it swells. The stretched hydrogel was created by mixing PVA with dimethyl sulfoxide (DMSO) and water to form a gel precursor solution, which was then gelatinized using the freeze-thaw method. This gel was soaked in the solution to replace the solvent within the gel. Afterward, the gel was stretched and dried. The unstressed PVA hydrogel was prepared by dissolving PVA in water, spin-coating the solution onto glass, and gelatinizing it using the cast-dry method. Carbon fibers were placed between the two sheets of dried hydrogel and laminated with a PVA and water solution. The electrodes are flat when dry, making it easy to place under the nerve. Additionally, it automatically deforms when water is applied, making installation easier than traditional electrodes (Figure 1c). It takes only about 30 seconds to completely encase the nerve. This functionality is expected to reduce the time required for surgery compared to traditional electrodes. The deformed hydrogel electrode is securely fixed due to the hydrogel's elasticity and does not move in a direction parallel to the nerve or dislocate vertically.Animal experiments were conducted by electrically stimulating the vagus nerve of pigs. During electrical stimulation, a bradycardia, which is a side effect of vagus nerve stimulation, was observed. This demonstrates the electrode's capability for stimulation.In conclusions, we developed the flexible electrodes that self-wraps around the nerves by exploiting the difference of the internal compression-expansion rate upon wetting. We confirmed that the wrapping force was large enough to stably fix the electrodes on the nerves while being small enough not to damage them. Finally, we tested the developed electrodes to stimulate the vagus nerve of pig and confirmed the effectiveness of the electrical stimulation. We hope that this electrode will be a significant step towards the practical use of hydrogel electrodes for stable fixation to the nerves and simplifying surgical procedures. In the future, we aim to further develop this technology and develop more advanced electrode designs that can be applied to various nerve stimulation treatments.Reference: Terutsuki. D, Yoroizuka. H, Osawa. S, Ogihara. Y, Abe. H, Nakagawa. A, Iwasaki. M, Nishizawa. M, “Totally Organic Hydrogel-Based Self-Closing Cuff Electrode for Vagus Nerve Stimulation.” Adv. Healthcare Mater. 2022, 11, 2201627.Fig.1 (a) Illustration of self-wrapping electrode. (b) Schematic diagram of electrode fabrication and self-wrapping mechanism. Light blue is freeze-thawed PVA hydrogel with DMSO pre-stretched before drying. Dark blue is cast-dried PVA hydrogel. (c) Image of wrapping an electrode around a nerve. The fabricated hydrogel electrode completely covers the nerve in about 30 seconds after water is applied. Figure 1

Magnetic vagus nerve stimulation ameliorates contrast-induced acute kidney injury by circulating plasma exosomal miR-365-3p

BackgroundContrast-induced acute kidney injury (CI-AKI) is manifested by a rapid decline in renal function occurring within 48–72 h in patients exposed to iodinated contrast media (CM). Although intravenous hydration is currently the effective method confirmed to prevent CI-AKI, it has several drawbacks. Some investigations have demonstrated the nephroprotective effects of vagus nerve stimulation (VNS) against kidney ischemia-reperfusion injury, but no direct research has investigated the use of VNS for treating CI-AKI. Additionally, most current VNS treatment applies invasive electrical stimulator implantation, which is largely limited by the complications. Our recent publications introduce the magnetic vagus nerve stimulation (mVNS) system pioneered and successfully used for the treatment of myocardial infarction. However, it remains uncertain whether mVNS can mitigate CI-AKI and its specific underlying mechanisms. Therefore, we herein evaluate the potential therapeutic effects of mVNS on CM-induced nephropathy in rats and explore the underlying mechanisms.ResultsmVNS treatment was found to significantly improve the damaged renal function, including the reduction of elevated serum creatinine (Scr), blood urea nitrogen (BUN), and urinary N-acetyl-β-D-glucosaminidase (NAG) with increased urine output. Pathologically, mVNS treatment alleviated the renal tissue structure injury, and suppressed kidney injury molecule-1 (KIM-1) expression and apoptosis in renal tubular epithelial cells. Mechanistically, increased circulating plasma exosomal miR-365-3p after mVNS treatment enhanced the autophagy and reduced CM-induced apoptosis in renal tubular epithelial cells by targeting Ras homolog enriched in brain (Rheb).ConclusionsIn summary, we demonstrated that mVNS can improve CI-AKI through enhanced autophagy and apoptosis inhibition, which depended on plasma exosomal miR-365-3p. Our findings highlight the therapeutic potential of mVNS for CI-AKI in clinical practice. However, further research is needed to determine the optimal stimulation parameters to achieve the best therapeutic effects.Graphical abstract

Possible Glycemic Effects of Vagus Nerve Stimulation Evaluated by Continuous Glucose Monitoring in People with Diabetes and Autonomic Neuropathy: A Randomized, Sham-Controlled Trial.

Objective: Autonomic neuropathy is associated with dysglycemia that is difficult to control. We investigated if transcutaneous vagus nerve stimulation (tVNS) could improve glycemic levels. Methods: We randomized 145 individuals with type 1 diabetes (T1D) (n = 70) or type 2 diabetes (T2D) (n = 75) and diabetic autonomic neuropathy (DAN) to self-administered treatment with active cervical tVNS (n = 68) or sham (n = 77) for 1 week (4 daily stimulations) and 8 weeks (2 daily stimulations), separated by a wash-out period of at least 2 weeks. Continuous glucose monitoring (CGM) indices were measured for 104 participants starting 5 days prior to intervention periods, during the 1-week period, and at end of the 8-week period. Primary outcomes were between-group differences in changes in coefficient of variation (CV) and in time in range (TIR 3.9-10 mmol/L). Secondary outcomes were other metrics of CGM and HbA1c. Results: For the 1-week period, median [interquartile range] changes of CV from baseline to follow-up were -1.1 [-4.3;2.0] % in active and -1.5 [-4.4;2.5] % in sham, with no significance between groups (P = 0.54). For TIR, the corresponding changes were 2.4 [-2.1;7.4] % in active and 5.1 [-2.6;8.8] in sham group (P = 0.84). For the 8-week treatment period, changes in CV and TIR between groups were also nonsignificant. However, in the subgroup analysis, persons with T1D receiving active tVNS for 8 weeks had a significant reduction in CV compared with the T1D group receiving sham stimulation (estimated treatment effect: -11.6 [95% confidence interval -20.2;-2.0] %, P = 0.009). None of the changes in secondary outcomes between treatment groups were significantly different. Conclusions: Overall, no significant changes were observed in CGM metrics between treatment arms, while individuals with T1D and DAN decreased their CV after 8 weeks of tVNS treatment.

Effects of vagal nerve stimulation parameters on heart rate variability in epilepsy patients.

Vagal nerve stimulation (VNS) is used as an alternative treatment in drug-resistant epilepsy patients. Effects of VNS on the cardiac autonomic system are controversial. In this study, we aimed to investigate the relationship between VNS parameters and heart rate variability (HRV) in epilepsy patients who underwent VNS treatment. Our study included 31 patients who underwent VNS for drug-resistant epilepsy. Patients were divided into groups according to response to VNS and VNS parameters. All patients underwent 24-h Holter ECG. The mean age of 31 VNS-treated epilepsy patients included in the study was 33.87 ± 7.6 years. When patients were grouped according to VNS response, 25 patients were in the VNS responder group and six patients were in the VNS-nonresponder group. When comparing Holter parameters in the VNS responder and non-responder groups, the median HF was significantly lower in the VNS responder group. VNS duration and signal frequency had a positive effect on LF/HF, while output and off time had a negative effect on LF/HF. When ROC analysis was performed to determine the cut-off values of the parameters for the VNS-responsive state, the AUC value of the HF parameter was 0.780, which was statistically significant. The cut-off value to distinguish response to VNS was 156.9. In conclusion, the effects of VNS parameters on HRV parameters are quite complex. However, the conclusion is that VNS is a neuromodulation method that affects the autonomic system in a complex way. Different levels of VNS parameters may also contribute to this effect. Furthermore, HRV parameters can be used as biomarkers to predict the patient population that may benefit from VNS.

Effects of long-term transcutaneous auricular vagus nerve stimulation on circadian vagal activity in people with Prader-Willi Syndrome: A case-series

BackgroundPrader-Willi Syndrome (PWS) is a genetic neurodevelopmental disorder marked by disruptions in circadian rhythms and autonomic nervous system (ANS) activity, hyperphagia, and episodes of emotional outbursts. Previous trials suggest that both invasive and non-invasive vagus nerve stimulation (VNS) can reduce emotional outbursts in PWS, potentially through its effects on vagal activity. AimThis case series investigated the effects of transcutaneous auricular VNS (taVNS) on cardiac markers of circadian vagal activity, specifically heart rate variability (HRV) and heart rate (HR), and their potential links to improvements in emotional outbursts. MethodsFive individuals with PWS (mean age: 26.9 years; 3 males, 2 females) received four hours of daily taVNS for 12 months, followed by one month of two-hour daily sessions. Outcome measures included daily recording of emotional outbursts and every three months 24-h HRV and HR recordings. Mixed cosinor models were applied to analyze changes in circadian rhythms of HRV and HR. A linear mixed model was used to assess the predictive value of cardiac vagal activity on emotional outbursts. ResultsCircadian amplitudes of HRV and HR were significantly higher at the end of the treatment compared to baseline (all p’s < .01). There was a significant increase in the rhythm-adjusted mean of HRV (p < .01), while the rhythm-adjusted HR mean significantly decreased, both indicating increased cardiac vagal activity. Higher rhythm-adjusted mean HRV predicted a lower number of emotional outbursts. ConclusionThe results suggest that taVNS may be effective by targeting ANS activity in individuals with PWS, contributing to improvements in behavioral regulation.

Advances in VNS efficiency and mechanisms of action on cognitive functions.

This systematic review aims to comprehensively analyze the efficacy and underlying mechanisms of vagus nerve stimulation (VNS) in enhancing cognitive functions and its therapeutic potential for various cognitive impairments. The review focuses on the impact of VNS on emotional processing, executive functions, learning, memory, and its clinical applications in conditions such as epilepsy, depression, Alzheimer's disease, and other neurological disorders. A systematic search of electronic databases (PubMed, Scopus, Web of Science) was conducted using the keywords "vagus nerve stimulation," "cognitive enhancement," "emotional processing," "executive function," "learning and memory," "epilepsy," "depression," "Alzheimer's disease," "neurological disorders," "attention-deficit/hyperactivity disorder," "sleep disorders," and "long COVID." The inclusion criteria encompassed controlled trials, longitudinal studies, and meta-analyses published in English between 2000 and July 2024. A comprehensive review of 100 articles highlighted the cognitive effects of Vagus Nerve Stimulation (VNS). Studies show that VNS, especially through transcutaneous auricular VNS (taVNS), enhances emotional recognition, particularly for facial expressions, and improves selective attention under high cognitive demands. Additionally, VNS enhances learning and memory, including associative memory and spatial working memory tasks. In clinical applications, VNS exhibits promising benefits for improving cognitive functions in treatment-resistant epilepsy, depression, and Alzheimer's disease. VNS represents a promising therapeutic approach for enhancing cognitive function across diverse patient populations. The reviewed evidence highlights its efficacy in modulating cognitive domains in healthy individuals and improving cognition in neurological conditions. However, the comparative effectiveness of different VNS modalities and the differential effects of online versus offline VNS on cognitive psychology require further investigation. Future research should focus on optimizing VNS protocols and elucidating specific cognitive domains that benefit most from VNS interventions. This ongoing exploration is essential for maximizing the therapeutic potential of VNS in clinical practice.

Anti-inflammatory Effects of Vagus Nerve Stimulation Are Mediated by the Notch Signaling Pathway during Sepsis-Associated AKI

Anti-inflammatory Effects of Vagus Nerve Stimulation Are Mediated by the Notch Signaling Pathway during Sepsis-Associated AKI

Vagus nerve stimulation with a small total charge transfer improves motor behavior and reduces neuroinflammation in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Conventional treatments are ineffective in reversing disease progression. Recently, the therapeutic and rehabilitation potential of vagus nerve stimulation (VNS) in PD has been explored. However, the underlying mechanisms remain largely unknown. In this study, we investigated the neuroprotective effects of VNS in a lateral lesioned mice model of PD. Excluding controls, experimental mice received cuff electrode implantation on the left vagus nerve and 6-hydroxydopamine administration into the bilateral striatum. After ten days, electrical stimulation was delivered for 11 consecutive days onto PD animals. Behavioral tests were performed after stimulation. The expression of TH, Iba-1, GFAP, adrenergic receptors and cytokines in the SN and striatum was detected by immunofluorescence or western blotting. The activity of noradrenergic neurons in the locus coeruleus (LC) was also measured. Our results suggest that VNS improved behavioral performance in rod rotation, open field tests and pole-climbing tests in PD mice, accompanied by a decrease in the loss of dopaminergic neurons in the SN and increased TH expression in the striatum. Neuroinflammation-related factors, such as GFAP, Iba-1, TNF-α and IL-1β were also suppressed in PD mice after VNS compared to those without treatment. Furthermore, the proportion of c-Fos-positive noradrenergic neurons in the LC increased when animals received VNS. Additionally, the expression of the adrenergic receptor of α1BR was also upregulated after VNS compared to PD mice. In conclusion, VNS has potential as a novel PD therapy for neuroprotective effects, and indicate that activation of norepinephric neurons in LC may plays an important role in VNS treatment for PD.

Transcutaneous vagus nerve stimulation effects on chronic pain: systematic review and meta-analysis.

Chronic pain is one of the major causes of disability with a tremendous impact on an individual's quality of life and on public health. Transcutaneous vagus nerve stimulation (tVNS) is a safe therapeutic for this condition. We aimed to evaluate its effects in adults with chronic pain. A comprehensive search was performed, including randomized controlled trials published until October 2023, which assessed the effects of noninvasive tVNS. Cohen's d effect size and 95% confidence intervals (CIs) were calculated, and random-effects meta-analyses were performed. Fifteen studies were included. The results revealed a mean effect size of 0.41 (95% CI 0.17-0.66) in favor of tVNS as compared with control, although a significant heterogeneity was observed (χ2 = 21.7, df = 10, P = 0.02, I 2 = 53.9%). However, when compared with nonactive controls, tVNS shows a larger effect size (0.79, 95% CI 0.25-1.33), although the number of studies was small (n = 3). When analyzed separately, auricular tVNS and cervical tVNS against control, it shows a significant small to moderate effect size, similar to that of the main analysis, respectively, 0.42 (95% CI 0.08-0.76, 8 studies) and 0.36 (95% CI 0.01-0.70, 3 studies). No differences were observed in the number of migraine days for the trials on migraine. This meta-analysis indicates that tVNS shows promise as an effective intervention for managing pain intensity in chronic pain conditions. We discuss the design of future trials to confirm these preliminary results, including sample size and parameters of stimulation.

The role of vagal nerve stimulation on psychosocial associated disorders in refractory epilepsy patients.

To determine the effects of vagal nerve stimulation on cognition and epilepsy-associated psychosocial problems in patients with intractable epilepsy, and to assess their relation to seizure decline. The longitudinal study was conducted at Saad Al-Witry Neurosciences Hospital, Baghdad, Iraq, from December 2015 to December 2020, and comprised refractory epilepsy cases with implanted vagal nerve stimulation devices. They were subjected to pre- and post-implantation epilepsy protocol assessment with added neuropsychological evaluation using the Mini-Mental State Examination system. Each case was followed up for 2 years post-implantation. Descriptive data regarding patient records of age, seizure nature, mental functioning level, and vagal nerve stimulation insertion was noted. Data was analysed using SPSS 21. Of the 150 patients, 75(50%) each were males and females, with 70(46.7%) aged <10 years at the time of surgery. Overall, 80(53.3%) patients had partial seizures with secondary generalisation, 70(46.7%) had refractory seizure attacks for <5 years, 78(52%) had attack frequency of 2-5 per day. All 150(100%) patients had had vagal nerve stimulation for >2 years. Post-intervention, 80(53.3%) patients had <2 attacks per day. Mini-Mental State Examination score was >25 in 35(23.3%) patients which post-intervention rose to 64(42.7%). There was evidence of improvement with respect to patient characteristics predictive of vagal nerve stimulation-related cognition and neuropsychological responsiveness in refractory epilepsy.

Effect of vagus nerve stimulation on emergency department utilization in children with drug-resistant epilepsy: a retrospective cohort study.

Epilepsy affects approximately 470,000 children in the United States. The estimated median incidence is 50.4 cases per 100,000 persons per year. There are approximately 3.1 million seizure-related emergency department (ED) visits per year among children. Vagus nerve stimulation (VNS) is a treatment option for drug-resistant epilepsy (DRE). While its primary goal is to decrease seizure burden, VNS may decrease seizure intensity and improve quality of life. The authors assessed whether VNS decreased the number of seizure-related ED visits in a cohort of children with DRE. The authors performed a retrospective chart review of pediatric patients (aged 0-21 years) who underwent implantation of a vagus nerve stimulator between January 2009 and January 2020 at the University of Pittsburgh Medical Center Children's Hospital of Pittsburgh. They used paired t-tests to assess differences in the number of ED visits 2 years before versus 2 years after VNS device implantation. Univariable linear regression analyses were used to test associations of preoperative characteristics with change in the number of ED visits following vagus nerve stimulator insertion. This study included 240 patients. Compared with patients without seizure-related ED visits before VNS, patients with ≥ 1 ED visits were younger in age at first VNS surgery (9.5 vs 10.8 years), had a shorter epilepsy duration before VNS surgery (5.8 vs 7.4 years), had a later year of device implantation (2014 vs 2012), and on average took more antiseizure medications (ASMs; 2.4 vs 2.1). There was no significant difference between the total number of seizure-related ED visits pre- versus post-VNS surgery (1.72 vs 1.59, p = 0.50), and no difference in status epilepticus-related visits (0.59 vs 0.46, p = 0.17). Univariable linear regression analyses revealed a mean change in ED visits of +0.3 for each year prior to 2022 and -0.5 for each additional ASM that patients took before vagus nerve stimulator insertion. This single-institution analysis demonstrated no significant change in the number of seizure-related ED visits within 2 years following VNS device implantation. Earlier VNS surgery was associated with more seizure-related ED visits after device insertion, suggesting that medical management and center experience may play a role in decreasing seizure-related ED visits. A greater number of ASMs was associated with fewer seizure-related ED visits after VNS device insertion, suggesting the role of medical management, patient baseline seizure threshold, and caregiver comfort with at-home seizure management.

Quantifying Vagus Nerve Stimulation Outcomes in Multifocal Refractory Epilepsy: A Model Across Multiple Surgeries.

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.

Integrating the 5-SENSE Score for Patient Selection in Vagus Nerve Stimulation for Drug-Resistant Epilepsy.

Addressing the challenge of drug-resistant epilepsy, our study offers a novel perspective by retrospectively applying the 5-SENSE score, initially created for stereoelectroencephalography (SEEG) planning, to evaluate its predictive value in patients undergoing vagus nerve stimulation (VNS) therapy. We conducted a comprehensive preoperative diagnostic work-up, including computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT), video-electroencephalogram (video-EEG), and clinical semiology. We then stratified 76 patients into three groups - low, moderate, and high focality - based on the focality of the seizure-onset zone. Such stratification was made to check the scoring ability in predictingVNStherapy seizure reduction. Our findings demonstrate an association between the extent of focality at the seizure-onset zone and the effectiveness of VNS, which may help to define the role of the 5-SENSE score in patient selection for VNS. This high dispersion of responses in the group with high focality reinforces the idea that outcome estimation is difficult and argues for an individualized strategy in the treatment of drug-resistant epilepsy. A study at the level of the 5-SENSE score indicates the importance of detailed preoperative assessments that may better optimize selection for VNS therapy and further improve clinical outcomes.