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Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer's disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer's Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters.

Objective: This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in MRL/lpr mice., Methods: MRL/lpr mice were treated with taVNS for ten weeks. Locus coeruleus (LC) tyrosine hydroxylase positive (TH + ) neurons were selectively lesioned by stereotactic injection of 6-hydroxydopamine (6-OHDA) or selectively activated by chemogenetic methods. Sympathetic denervation was conducted by intraperitoneal injection of 6-OHDA., Results: TaVNS activated the TH  +  neurons in LC. TaVNS produced central therapeutic effects by reducing the number of hippocampal microglia, and increasing the number of surviving LC TH + neurons in MRL/lpr mice. TaVNS also retarded the development of lymphadenectasis and splenomegaly, decreased the proportion of double-negative T (DNT) cells, and alleviated nephritis in MRL/lpr mice. The lesion of LC TH + neurons eliminated both these central and peripheral therapeutic effects of taVNS, while chemogenetic activation of LC TH + neurons mimicked most central and peripheral protective effects of taVNS in MRL/lpr mice. Furthermore, taVNS regulated the autonomic nervous system in MRL/lpr mice., Conclusion: This study provides direct evidence that taVNS can retard the development of peripheral and central symptoms of SLE, which is mediated by the LC TH + neurons., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “Locus coeruleus tyrosine hydroxylase positive neurons mediated the peripheral and central therapeutic effects of transcutaneous auricular vagus nerve stimulation (taVNS) in MRL/lpr mice”., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vagus nerve stimulation (VNS) is a non-pharmacological treatment of refractory epilepsy, which also has an antidepressive effect. The favorable combinations of VNS with specific mechanisms of action of antiseizure medication (ASM) on mood and health-related quality of life (HrQol) have not yet been studied. The objective was to identify favourable combinations of specific ASMs with VNS for the HrQoL and depression in refractory epilepsy., Methods: We performed an observational study including patients with refractory epilepsy and an implanted VNS (N = 151). In the first 24 months after VNS implantation, all patients were on stable ASM therapy. We used the standardized questionnaires QOLIE10, EQVAS and EQ5D to evaluate HrQoL as well as the Beck Depression Inventory (BDI). Multiple regression analysis was performed to evaluate the synergistic combinations of ASM with VNS for HrQoL., Results: At the year-two follow-up (N = 151, age 45.2 ± 17.0 years), significant improvement (p < 0.05) in BDI scores was found for combination of VNS with SV2A modulators (58.4 %) or AMPA antagonists (44.4 %). A significant increase of HrQoL by at least 30 % (p < 0.05) was measured for a combination of VNS with SV2A modulators (brivaracetam, levetiracetam) or slow sodium channel inhibitors (eslicarbazepine, lacosamide)., Conclusion: The results of our study suggests a favorable effect of the combination of SV2A modulators or slow sodium channel inhibitors with VNS on the HrQoL in comparison to other ASMs. Besides the possible synergistic effects on the seizure frequency, the amelioration of behavioral side effects of SV2A modulators by VNS is an important factor of HrQoL-improvement in these combinations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Vagal neurostimulation (VNS) medical devices (MDs) are used to treat drug-resistant epilepsy. Using a magnet, the patient can activate on the stimulations in order to stop a seizure or interrupt the adverse effects (AEs) of the device. The objective is to evaluate the improvement of the patients' knowledge about the VNS following a pharmaceutical educational interview (PEI) as well as their satisfaction., Materials and Methods: The pharmaceutical educational interview regarding drugs and DMs was performed by the clinical pharmacist at the patient's bed after VNS implantation. A questionnaire about VNS devices (operation, adverse effects, recommendations) and assessing knowledge was submitted to patients before and after the PEI. Satisfaction was assessed by the Likert scale., Results: From March 2020 to August 2021, 18 implanted patients were included in the study. In 78% of cases (14/18), the total number of good responses after PEI increased. The mean good response was significantly increased from 16.11/25 (64%) before PEI to 22.33/25 (89%) after PEI (P-value<0.01). The maximum satisfaction score (4/4) was given in 71% of the items., Discussion-Conclusion: The results support the relevance of PEI. Patients feel a need for information and consider the interview useful. An improvement in knowledge was observed, which allows us to hope for an optimization of the effectiveness of the device, in particular, a reduction in seizures and AE. This study shows the feasibility and the interest of the development of clinical pharmacy applied to medical devices in complementarity with the expertise on drugs., (Copyright © 2023 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: Transcutaneous auricular vagus nerve stimulation (taVNS) was performed in two patients suffering structural focal epilepsy with preserved intellectual ability to show the feasibility of taVNS for specific patient groups., Case Presentations: Patient 1 was a 24-year-old woman with frontal lobe epilepsy who had weekly hyperkinetic seizures despite multiple anti-seizure medications. Patient 2 was a 27-year-old woman with parietal lobe epilepsy and focal cortical dysplasia in the vicinity of the lipoma in the corpus callosum. She experienced weekly focal-impaired awareness seizures even with anti-seizure medication. taVNS was applied to the left earlobe of both patients at 1.5 mA, 25 Hz, 250 μs pulse width, and 30 s stimulation with 30 s rest for 4 h per day. Over an 8-week baseline and 20 weeks of stimulation, the rate of reduction in seizure frequency was evaluated, along with quality-of-life using the Short-Form 36-Item Health survey., Results: At baseline, we measured up to 11 and 12 focal seizures per week in Patient 1 and 2, respectively, with both patients achieving seizure freedom after 4 and 20 weeks taVNS, respectively. Patient 1 and 2 were observed for 18 and 14 months, respectively, including the clinical trial and follow-up observation period. Quality-of-life ratings increased in both patients, and no significant adverse events occurred during the study period. During the maintenance period after 20 weeks, seizures remained absent in Patient 1, and seizures remained reduced in Patient 2., Conclusion: Our results demonstrate that taVNS may be a promising tool for structural focal epilepsy with preserved cognitive function. A multicenter double-blind clinical trial is needed to confirm the role of taVNS as an anti-seizure tool., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: The objective was to systematically evaluate the current evidence surrounding the effect of vagus nerve stimulation (VNS) on quality of sleep and obstructive sleep apnea (OSA) among patients with epilepsy., Methods: A literature search was conducted using the Embase and MEDLINE databases. Studies were included if they involved patients with drug-resistant epilepsy treated with VNS and used validated tools to report on quality of sleep or sleep apnea. The literature search yielded 112 citations related to VNS and sleep quality, and 82 citations related to sleep apnea. Twelve articles were included in the review, of which five measured quality of sleep among patients who underwent VNS, six studies measured sleep apnea, and one study measured both outcomes., Results: Studies measuring quality of sleep used different methods, including sleep quality questionnaires and the percentage of sleep in each cycle. Studies also varied in patient populations, the use of control groups, and whether multiple measurements were taken for each patient. Some studies found improved sleep quality after VNS, whereas others found reductions in deep sleep stages. Additionally, mixed results in sleep quality were found when comparing patients with epilepsy who received VNS treatment versus patients with epilepsy who did not receive VNS treatment. Variables such as VNS intensity and age could potentially confound quality of sleep. Studies measuring sleep apnea consistently found increased proportions of patients diagnosed with OSA or increased sleep index scores after VNS implantation., Significance: Overall, the effect of VNS on quality of sleep remains unclear, as studies were very heterogeneous, although the effect on sleep apnea has consistently shown an increase in sleep apnea severity indices after VNS implantation. Future studies with consistent measures and discussions of confounding are required to determine the effect of VNS on quality of sleep, and the effect of VNS parameters should be further explored among patients who develop sleep apnea., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Surgically implanted neurostimulation devices for the treatment of depression have been studied for the last three decades. While the surgical risk associated with these treatment approaches clearly limits their use to the most severely impacted depressed patients, they offer a unique opportunity to better understand the impact of relatively localized alteration of neural activity in patient groups. As a result, these approaches provide a strict test of the role of individual neural structures or networks in mechanistic models of depression. In this chapter, we review the proposed mechanisms of action and evidence for clinical efficacy of vagal nerve stimulation, deep brain stimulation, and epidural cortical stimulation in patients with depression. The evidence for efficacy remains limited for all three modalities, but the long-term follow-up studies of treated patients have highlighted the importance of interactions between neural regions in determining therapeutic response, and suggest that personalized approaches to stimulation are likely to be required., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

As the pathophysiological mechanisms of vagus nerve stimulation (VNS) causing individual differences in the vagal ascending network remains unclear, stereoelectroencephalography (SEEG) provides a unique platform to explore the brain networks affected by VNS and helps to understand the anti-seizure mechanism of VNS more comprehensively. This study presents a preliminary exploration of the acute effect of VNS. SEEG signals were collected to assess the acute effect of VNS on neural synchronization in patients with drug-resistant epilepsy, especially in epileptogenic networks. The results show that the better the efficacy of VNS, the wider the spread of desynchronization assessed by weighted phase lag index at a high frequency band caused by VNS. Future studies should focus on the association between the change in synchronization and the efficacy of VNS, exploring the possibility of synchronization as a biomarker for patient screening and parameter programming., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this study, it was aimed to investigate the effects of switching off stimulation on time perception in patients with drug-resistant epilepsy who underwent Vagal Nerve Stimulation (VNS). In accordance with the literature, a cognitive battery of tests for motor timing and perceptual timing was utilized. Computerized time perception tests; Paced Motor Timing Test, Duration Discrimination Test, Temporal Reproduction Test, and Time Estimation Test were administered to the patients while VNS was on and off. A total of 14 patients who met the inclusion criteria of 23 VNS patients followed in the Epilepsy Outpatient Clinic were included in the study. In the Temporal Reproduction Test, for time durations of 1000 ms (ms), 2000 ms, 3000 ms, 4000 ms, and 5000 ms the comparison of reported time values between VNS on and VNS off yielded respective p values; p = 0.73, p = 0.03, p = 0.176, p = 0.418, p = 0,873. The reported time is thus significantly shorter only for 2000 ms when the VNS was on. Positive effect of VNS on attention, alertness and focusing are expected to cause acceleration of the internal clock resulting in perceiving time running slower than actual. In our study, it was concluded that the internal clock runs faster when the VNS is on, and time is perceived as running slower than it actually is. This result can also be accepted as an indirect indicator of increased attention in the period when VNS is on., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Vagus nerve stimulation (VNS) is a potential treatment option for gastrointestinal (GI) diseases. The present study aimed to understand the physiological effects of VNS on gastrointestinal (GI) function, which is crucial for developing more effective adaptive closed-loop VNS therapies for GI diseases. Electrogastrography (EGG), which measures gastric electrical activities (GEAs) as a proxy to quantify GI functions, was employed in our investigation. We introduced a recording schema that allowed us to simultaneously induce electrical VNS and record EGG. While this setup created a unique model for studying the effects of VNS on the GI function and provided an excellent testbed for designing advanced neuromodulation therapies, the resulting data was noisy, heterogeneous, and required specialized analysis tools. The current study aimed at formulating a systematic and interpretable approach to quantify the physiological effects of electrical VNS on GEAs in ferrets by using signal processing and machine learning techniques. Our analysis pipeline included pre-processing steps, feature extraction from both time and frequency domains, a voting algorithm for selecting features, and model training and validation. Our results indicated that the electrophysiological changes induced by VNS were optimally characterized by a distinct set of features for each classification scenario. Additionally, our findings demonstrated that the process of feature selection enhanced classification performance and facilitated representation learning., Competing Interests: No authors have competing interests., (Copyright: © 2023 Zeydabadinezhad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: In this randomized, double-blind, sham-controlled trial, we explored the effect of 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on gait impairments in Parkinson's disease (PD) patients and investigated the underlying neural mechanism., Methods: In total, 22 PD patients and 14 healthy controls were enrolled. PD patients were randomized (1:1) to receive active or sham taVNS (same position as active taVNS group but without releasing current) twice a day for 1 week. Meanwhile, all subjects were measured activation in the bilateral frontal and sensorimotor cortex during usual walking by functional near-infrared spectroscopy., Results: PD patients showed instable gait with insufficient range of motion during usual walking. Active taVNS improved gait characteristics including step length, stride velocity, stride length, and step length variability compared with sham taVNS after completion of the 7-day therapy. No difference was found in the Unified Parkinson's Disease Rating Scale III, Timed Up and Go, Tinetti Balance, and Gait scores. Moreover, PD patients had higher relative change of oxyhemoglobin in the left dorsolateral prefrontal cortex, pre-motor area, supplementary motor area, primary motor cortex, and primary somatosensory cortex than HCs group during usual walking. Hemodynamic responses in the left primary somatosensory cortex were significantly decreased after taVNS therapy., Conclusion: taVNS can relieve gait impairments and remodel sensorimotor integration in PD patients., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: It is aimed to examine the potential benefits and effects of the use of transcutaneous auricular vagus nerve stimulation (VNS) for sporting purposes on recovery, fatigue, and sportive performance level., Methods: In this study, 90 people between the ages of 18-23 were participated. They were randomly divided into three groups as bilateral sham, unilateral left, and bilateral VNS. A 4-day protocol was applied to the participants. Cycling exercise was performed with maximum performance for 30 min under the same watt load. Pulse, systolic and diastolic blood pressure, distance, pain, fatigue, lactic acid level, and autonomic nervous system were evaluated., Results: Within the groups, there was a statistically significant difference between the data (p < .05) except for the distance covered parameter. When we compare the groups, in addition to the distance traveled in all groups, there is no statistically significant difference in the 1st day 1st measurement and 2nd measurement data of all parameters (p > .05 When we compared the data according to days, there was a statistically significant difference between bilateral stimulation (BS) and unilateral stimulation, only pain and fatigue levels (p < .05)., Conclusion: In our study, we saw that BS application gave positive results in reducing pain and fatigue due to cycling exercise compared to other applications. Similar results were obtained when we evaluated the data on a daily basis. We believe that VNS will be beneficial in reducing pain and fatigue, especially during and after the competition halftime., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Purpose: Patients with severe drug-resistant epilepsy (DRE) experience psychomotor disorders. Our study aimed to assess the psychomotor outcomes after vagus nerve stimulation (VNS) in this population., Methods: We prospectively evaluated psychomotor function in 17 adult patients with severe DRE who were referred for VNS. Psychomotor functions were examined, in the preoperative period and at 18 months post-surgery, by a psychomotor therapist using a full set of the following specific tests: the Rey-Osterrieth complex figure (ROCF) test, the Zazzo's cancelation task (ZCT), the Piaget-Head test and the paired images test., Results: At 18 months post-VNS surgery, the Piaget-head scores increased by 3 points (p = 0.008) compared to baseline. Performances were also improved for ROCF test both in copy (+2.4 points, p = 0.001) and recall (+2.0 points, p = 0.008) tasks and for the paired images test (accuracy index: +28.6 %, p = 0.03). Regarding the ZCT findings, the efficiency index increased in both single (+16 %, p = 0.005) and dual (+17.1 %, p < 0.001) tasks. QoL improved in 88.2 % of patients., Conclusions: Patients with severe DRE treated with VNS experienced improved performance in terms of global psychomotor functions. Perceptual organization, visuospatial memory, laterality awareness, sustained attention, concentration, visual scanning, and inhibition were significantly improved., Competing Interests: Declaration of Competing Interest Dr. Bertrand Mathon has received support from Medtronic and Livanova companies. The other authors have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose of Review: Vagal nerve stimulation (VNS) is emerging as a probable therapeutic option for headache. Several questions remain on the mechanism of action, device parameters, efficacy, duration of treatment and long-term safety. This review aims at describing findings of recent literature pertaining to VNS for headache, to put these findings into the perspective of our current fund of knowledge and future scope of work on the topic., Recent Findings: Several studies on functional magnetic resonance imaging patterns following VNS in patients with headache have been published, revealing potential biomarkers of headache and possible treatment effects. A study on post-COVID-19 headache and its management with noninvasive cervical VNS adds to the body of original studies. Meta-analyses and systematic reviews outlining previous work have been published. The collection of these studies adds some data to mechanisms of VNS without adding much insight to differential effects of sub-types of VNS and possible device settings that could prove to be beneficial for headache management., Summary: Well designed studies are needed to identify mechanisms of action, elicit differential effects of various stimulation parameters, and to demonstrate long-term therapeutic effects and safety of VNS in headache., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Vagus nerve stimulation (VNS) has emerged as a potential therapeutic approach for neurological and psychiatric disorders. In recent years, there has been increasing interest in VNS for treating ischemic stroke. This review discusses the evidence supporting VNS as a treatment option for ischemic stroke and elucidates its underlying mechanisms., Recent Findings: Preclinical studies investigating VNS in stroke models have shown reduced infarct volumes and improved neurological deficits. Additionally, VNS has been found to reduce reperfusion injury. VNS may promote neuroprotection by reducing inflammation, enhancing cerebral blood flow, and modulating the release of neurotransmitters. Additionally, VNS may stimulate neuroplasticity, thereby facilitating post-stroke recovery. The Food and Drug Administration has approved invasive VNS (iVNS) combined with rehabilitation for ischemic stroke patients with moderate to severe upper limb deficits. However, iVNS is not feasible in acute stroke due to its time-sensitive nature. Non-invasive VNS (nVNS) may be an alternative approach for treating ischemic stroke. While the evidence from preclinical studies and clinical trials of nVNS is promising, the mechanisms through which VNS exerts its beneficial effects on ischemic stroke are still being elucidated. Therefore, further research is needed to better understand the efficacy and underlying mechanisms of nVNS in ischemic stroke. Moreover, large-scale randomized clinical trials are necessary to determine the optimal nVNS protocols, assess its long-term effects on stroke recovery and outcomes, and identify the potential benefits of combining nVNS with other rehabilitation strategies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Epilepsy is the most common brain disorder around the world. The main treatments of epilepsy are through drug treatment or epilepsy surgery. However, examples of EEG-based neuromodulation treatments, such as Vagus nerve stimulation (VNS), thalamic deep brain stimulation (DBS), and responsive neuro-stimulation (RNS), are also promising therapeutic methods nowadays. The aim of the paper is to recognize the effectiveness and potential risks of the three techniques. By carrying out randomized multicenter double-blind trials, this research studied the effectiveness of VNS, RNS, and DBS by measuring the median seizure reduction rate, rate of the responder, and proportion of seizure-free patients; the sudden unexpected death in epilepsy (SUDEP) of the treated patients; and the possible side effects that each treatment may cause. This review paper discusses the classification of epilepsy, common treatment methods for epilepsy, previous studies related to the three techniques, and data collected from the randomized multicenter double-blind trials. All in all, the result suggested that for short-term treatment, DBS may be the most effective method, but for long-term treatment, RNS may be more recommended. As the SUDEP rates for all three methods are lower than the SUDEP rate for epilepsy surgery, EEG-based neuromodulation techniques may become the main treatment for epilepsy in the future.

Opioid use disorder (OUD) is a critical problem in China and is accompanied by depression and deficits in cognitive control. In China, the most successful intervention for OUD is the community drug rehabilitation where methadone maintenance treatment (MMT) plays a key role. Even though methadone for the treatment of OUD can be helpful, it can cause severe somatic side-effects, which limit its effectivity. Even worse, it can have detrimental effects on cognitive control, which is crucial to regain control over drug intake. Here, we consider the potential use of auricular transcutaneous vagus nerve stimulation (atVNS) as an addition to MMT for opioid withdrawal treatment. Compared to other non-invasive brain stimulation methods, atVNS also targets the locus coeruleus (LC) important for noradrenaline (NA) synthesis. NA is an essential neurotransmitter impacted in opioid withdrawal and also critically involved in cognitive control processes. Its ADD-ON to MMT might be a useful mean to improve mood and enhance cognitive control processes impacted in OUD. We discuss the translational advantages of atVNS in China such as the cultural acceptance of the modality of treatment similar to electroacupuncture. Additionally, the wearability of the ear electrode and at-home self-administration without intense medical supervision makes of atVNS a useful tool to enhance clinical and cognitive outcomes especially in everyday life situation. We discuss how atVNS can be integrated in tele-medical health approaches allowing that innovative treatments can widely be disseminated and continued even in situations of restricted medical access., (© 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Cardiovascular diseases remain the leading cause of death globally. In recent years, vagal nerve stimulation (VNS) has shown promising results in the treatment of a number of cardiovascular diseases. In this approach, mild electrical pulses are sent to the brain via the vagus nerve. This open-loop neurostimulation, however, leads to various side effects due to physiological and inter-patient variability and therefore a closed-loop delivery strategy of electrical pulses that accounts for this variability is desired. In this context, we envision data-driven sparse dynamical model parameterized by patient-specific data as appropriate for use in closed loop controller design. In this work, we build a dynamical model for mean arterial pressure and heart rate using the method sparse identification of nonlinear dynamics (SINDy). As a proxy for real datasets or measurements from a patient, we simulate a mechanistic model from the literature and then discover a data-driven model for predicting mean arterial pressure and heart rate in response to neural stimulus. This discovered model is then used to design a controller to be implemented in closed-loop via model predictive control. We observe that this data-driven model is interpretable, consistent with experiments, provides insights on the sensitivity of different stimulation locations and simplifies the formulation of the optimal control problem. Noting the set-point tracking performance of this closed-loop model-based controller that uses this discovered model, we conclude that the model is adequate in capturing the dynamics of a highly nonlinear cardiovascular system for the purpose of optimal predictive controller design., Competing Interests: Declaration of competing interest The authors do not have any conflict of interest to declare with respect to the results presented in the submitted manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The autonomic response to transcutaneous auricular vagus nerve stimulation (taVNS) has been linked to the engagement of brainstem circuitry modulating autonomic outflow. However, the physiological mechanisms supporting such efferent vagal responses are not well understood, particularly in humans., Hypothesis: We present a paradigm for estimating directional brain-heart interactions in response to taVNS. We propose that our approach is able to identify causal links between the activity of brainstem nuclei involved in autonomic control and cardiovagal outflow., Methods: We adopt an approach based on a recent reformulation of Granger causality that includes permutation-based, nonparametric statistics. The method is applied to ultrahigh field (7T) functional magnetic resonance imaging (fMRI) data collected on healthy subjects during taVNS., Results: Our framework identified taVNS-evoked functional brainstem responses with superior sensitivity compared to prior conventional approaches, confirming causal links between taVNS stimulation and fMRI response in the nucleus tractus solitarii (NTS). Furthermore, our causal approach elucidated potential mechanisms by which information is relayed between brainstem nuclei and cardiovagal, i.e., high-frequency heart rate variability, in response to taVNS. Our findings revealed that key brainstem nuclei, known from animal models to be involved in cardiovascular control, exert a causal influence on taVNS-induced cardiovagal outflow in humans., Conclusion: Our causal approach allowed us to noninvasively evaluate directional interactions between fMRI BOLD signals from brainstem nuclei and cardiovagal outflow., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vagus nerve stimulation (VNS) is a therapeutic option in drug-resistant epilepsy. VNS leads to ≥ 50% seizure reduction in 50 to 60% of patients, termed "responders". The remaining 40 to 50% of patients, "non-responders", exhibit seizure reduction < 50%. Our work aims to differentiate between these two patient groups in preimplantation EEG analysis by employing several Entropy methods. We identified 59 drug-resistant epilepsy patients treated with VNS. We established their response to VNS in terms of responders and non-responders. A preimplantation EEG with eyes open/closed, photic stimulation, and hyperventilation was found for each patient. The EEG was segmented into eight time intervals within four standard frequency bands. In all, 32 EEG segments were obtained. Seven Entropy methods were calculated for all segments. Subsequently, VNS responders and non-responders were compared using individual Entropy methods. VNS responders and non-responders differed significantly in all Entropy methods except Approximate Entropy. Spectral Entropy revealed the highest number of EEG segments differentiating between responders and non-responders. The most useful frequency band distinguishing responders and non-responders was the alpha frequency, and the most helpful time interval was hyperventilation and rest 4 (the end of EEG recording)., (© 2023. The Author(s).)

Purpose: A retrospective study, based on a prospectively built database, presents the results of long-term follow-up care of pediatric vagus nerve stimulation (VNS) patients in terms of seizure outcome, surgical aspects, the potential impact of maturation, and medication changes., Methods: From a prospectively built database, 16 VNS patients (median age 12.0 years, range 6.0 to 16.0 years; median seizure duration 6.5 years, range 2.0 to 15.5 years) followed for at least 10 years were graded as non-responder - NR (seizure frequency reduction < 50%), responder - R (reduction ≥ 50% and < 80%), and 80% responder - 80R (reduction ≥ 80%). Data about surgical aspects (battery replacement, system complications), seizure dynamics, and medication changes were taken from the database., Results: The early percentages of good results (80R + R) were 43.8% (year 1), 50.0% (year 2), and 43.8% (year 3). These percentages remained stable between years 10 and 12 (50% year 10; 46.7% year 11; 50% year 12) and increased in years 16 (60%) and 17 (75%). Depleted batteries were replaced in ten patients, six of whom were either R or 80R. In the four NR, the indication for replacement was improved quality of life. Three patients had VNS explanted or switched off-one had repeated asystolia and two were NR. The effect of hormonal changes in menarche on seizure was not proven. During the study, antiseizure medication was changed in all patients., Conclusions: The study proved the efficacy and safety of VNS in pediatric patients over an exceptionally long follow-up period. The demand for battery replacements indicates a positive treatment effect., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To determine whether transcutaneous auricular vagus nerve stimulation (taVNS) paired with twice daily bottle feeding increases the volume of oral feeds and white matter neuroplasticity in term-age-equivalent infants failing oral feeds and determined to need a gastrostomy tube., Study Design: In this prospective, open-label study, 21 infants received taVNS paired with 2 bottle feeds for 2 - 3 weeks (2x). We compared 1) increase oral feeding volumes with 2x taVNS and previously reported once daily taVNS (1x) to determine a dose response, 2) number of infants who attained full oral feeding volumes, and 3) diffusional kurtosis imaging and magnetic resonance spectroscopy before and after treatment by paired t tests., Results: All 2x taVNS treated infants significantly increased their feeding volumes compared with 10 days before treatment. Over 50% of 2x taVNS infants achieved full oral feeds but in a shorter time than 1x cohort (median 7 days [2x], 12.5 days [1x], P < .05). Infants attaining full oral feeds showed greater increase in radial kurtosis in the right corticospinal tract at the cerebellar peduncle and external capsule. Notably, 75% of infants of diabetic mothers failed full oral feeds, and their glutathione concentrations in the basal ganglia, a measure of central nervous system oxidative stress, were significantly associated with feeding outcome., Conclusions: In infants with feeding difficulty, increasing the number of daily taVNS-paired feeding sessions to twice-daily significantly accelerates response time but not the overall response rate of treatment. taVNS was associated with white matter motor tract plasticity in infants able to attain full oral feeds., Trial Registration: Clinicaltrials.gov (NCT04643808)., Competing Interests: Declaration of Competing Interest National Institutes of Health National Center of Neuromodulation for Rehabilitation NIH/NICHD Grant #P2CHD086844 (Kautz, PI; Pilot award to DDJ); National Institutes of Health Center of Biomedical Research Excellence (COBRE) in Stroke Recovery, Grant #P20GM109040 (Kautz, PI; Pilot award to DDJ); NIH/NINDSF31NS108623 (to HGM). B.W.B, M.S.G, D.C, and D.D.J are named inventors of a patent related to this work, which is assigned to the Medical University of South Carolina. The other authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Refractory idiopathic generalised epilepsy (IGE; also known as genetic generalised epilepsy) is a clinical challenge due to limited available therapeutic options. While vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant focal epilepsy, there is limited evidence supporting its efficacy for refractory IGE., Methods: We conducted a single-centre retrospective analysis of adult IGE patients treated with VNS between January 2003 and January 2022. We analysed the efficacy, safety, tolerability, stimulation parameters and potential clinical features of VNS response in this IGE cohort., Results: Twenty-three IGE patients were implanted with VNS between January 2003 and January 2022. Twenty-two patients (95.65%) were female. The median baseline seizure frequency was 30 per month (interquartile range [IQR]= 140), including generalised tonic-clonic seizures (GTCS), absences, myoclonus, and eyelid myoclonia with/without absences. The median number of baseline anti-seizure medications (ASM) was three (IQR= 2). Patients had previously failed a median of six ASM (IQR= 5). At the end of the study period, VNS therapy remained active in 17 patients (73.9%). amongst patients who continued VNS, thirteen (56.5% of the overall cohort) were considered responders (≥50% seizure frequency reduction). Amongst the clinical variables analysed, only psychiatric comorbidity correlated with poorer seizure outcomes, but was non-significant after applying the Bonferroni correction. Although 16 patients reported side-effects, none resulted in the discontinuation of VNS therapy., Significance: Over half of the patients with refractory IGE experienced a positive response to VNS therapy. VNS represents a viable treatment option for patients with refractory IGE, particularly for females, when other therapeutic options have been exhausted., Competing Interests: Conflicts of interest JPC served as a speaker and received travel expenses from Angelini Pharma. PBM served on an advisory board for Angelini Pharma and received travel expenses from UCB Pharma. AV, COD, NC, BL, BSG, PE, RG, GM, DJC, CPD, KJS, HEN, RDK, and DOB reported no conflicts of interest. Over the last three years, PWW has served as a speaker for Angelini Pharma, and ND has served as a paid advisor and/or speaker for Angelini Pharma, Eisai, Radius Pharma, and UNEEG Medical., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: Although vagus nerve stimulation (VNS) is a common and widely used therapy for pharmacoresistant epilepsy, the reported efficacy of VNS in pediatric patients varies, so it is unclear which children will respond to VNS therapy. This study aimed to identify functional brain network features associated with VNS action to distinguish VNS responders from nonresponders using scalp electroencephalogram (EEG) data., Methods: Twenty-three children were included in this study, 16 in the discovery cohort and 7 in the test cohort. Using partial correlation value as a measure of whole-brain functional connectivity, we identified the differential edges between responders and nonresponders. Results derived from this were used as input to generate a support vector machine-learning classifier to predict VNS outcomes., Results: The postcentral gyrus in the left and right parietal lobe regions was identified as the most significant differential brain region between VNS responders and nonresponders (p < 0.001). The resultant classifier demonstrated a mean AUC value of 0.88, a mean sensitivity rate of 91.4%, and a mean specificity rate of 84.3% on fivefold cross-validation in the discovery cohort. In the testing cohort, our study demonstrated an AUC value of 0.91, a sensitivity rate of 86.6%, and a specificity rate of 79.3%. Furthermore, for prediction accuracy, our model can achieve 81.4% accuracy at the epoch level and 100% accuracy at the patient level., Significance: This study provides the first treatment response prediction model for VNS using scalp EEG data with ictal recordings and offers new insights into its mechanism of action. Our results suggest that brain functional connectivity features can help predict therapeutic response to VNS therapy. With further validation, our model could facilitate the selection of targeted pediatric patients and help avoid risky and costly procedures for patients who are unlikely to benefit from VNS therapy., (© 2023 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective. This study aims to develop a comprehensive decoding framework to create a multivariate physiological model of vagus nerve transmission that reveals the complex interactions between the nervous and metabolic systems. Approach. Vagus nerve activity was recorded in female Sprague-Dawley rats using gold hook microwires implanted around the left cervical vagus nerve. The rats were divided into three experimental cohorts (intact nerve, ligation nerve for recording afferent activation, and ligation for recording efferent activation) and metabolic challenges were administered to change glucose levels while recording the nerve activity. The decoding methodology involved various techniques, including continuous wavelet transformation, extraction of breathing rate (BR), and correlation of neural metrics with physiological signals. Main results. Decrease in glucose level was consistently negatively correlated with an increase in the firing activity of the intact vagus nerve that was found to be conveyed by both afferent and efferent pathways, with the afferent response being more similar to the one on the intact nerve. A larger variability was observed in the sensory and motor responses to hyperglycaemia. A novel strategy to extract the BR over time based on inter-burst-interval is also presented. The vagus afferent was found to encode breathing information through amplitude and firing rate modulation. Modulations of the signal amplitude were also observed due to changes in heart rate in the intact and efferent recordings, highlighting the parasympathetic control of the heart. Significance. The analytical framework presented in this study provides an integrative understanding that considers the relationship between metabolic, cardiac, and breathing signals and contributes to the development of a multivariable physiological model for the transmission of vagus nerve signals. This work progresses toward the development of closed-loop neuro-metabolic therapeutic systems for diabetes., (Creative Commons Attribution license.)

Vagus nerve stimulation (VNS) has been found to exert anti-inflammatory effects in different clinical settings and has been associated with improvement of clinical outcomes. However, evidence on the mechanistic link between the potential association of inflammatory status with clinical outcomes following VNS is scarce. This review aims to summarize the existing knowledge linking VNS with inflammation and its potential link with major outcomes in cardiovascular diseases, in both preclinical and clinical studies. Existing data show that in the setting of myocardial ischemia and reperfusion, VNS seems to reduce inflammation resulting in reduced infarct size and reduced incidence of ventricular arrhythmias during reperfusion. Furthermore, VNS has a protective role in vascular function following myocardial ischemia and reperfusion. Atrial fibrillation burden has also been reduced by VNS, whereas suppression of inflammation may be a potential mechanism for this effect. In the setting of heart failure, VNS was found to improve systolic function and reverse cardiac remodeling. In summary, existing experimental data show a reduction in inflammatory markers by VNS, which may cause improved clinical outcomes in cardiovascular diseases. However, more data are needed to evaluate the association between the inflammatory status with the clinical outcomes following VNS.

We propose a nonlinear model-based control technique for regulating the heart rate and blood pressure using vagus nerve neuromodulation. The closed-loop framework is based on an in silico model of the rat cardiovascular system for the simulation of the hemodynamic response to multi-location vagal nerve stimulation. The in silico model is derived by compartmentalizing the various physiological components involved in the closed-loop cardiovascular system with intrinsic baroreflex regulation to virtually generate nominal and hypertension-related heart dynamics of rats in rest and exercise states. The controller, using a reduced cycle-averaged model, monitors the outputs from the in silico model, estimates the current state of the reduced model, and computes the optimum stimulation locations and the corresponding parameters using a nonlinear model predictive control algorithm. The results demonstrate that the proposed control strategy is robust with respect to its ability to handle setpoint tracking and disturbance rejection in different simulation scenarios.

Introduction: Vagus nerve stimulation (VNS) is a neuromodulation therapy for drug-resistant epilepsy (DRE), refractory status epilepticus, and treatment-resistant depression. The lead is tunneled into the subcutaneous space and connected to the generator, which is usually implanted in a subcutaneous pocket below the clavicle. Surgical complications in the chest region include skin breakdown or infection. An alternative approach is to perform a subclavear subpectoral implantation. In our surgical series, we report a new aesthetic implantation method for VNS generators in children and young patients: the transaxillary subpectoral placement., Materials and Methods: From May 2021 to May 2023, 10 vagus nerve stimulation generators were placed subpectorally with a transaxillary approach by the authors. We considered operative time, surgical complications such as blood loss, infections, device migration, pain, and adverse events at follow-up., Results: In this surgical series, we reviewed all cases of subpectoral implantation of VNS generators in children and young adults at our institution in the last 2 years. All patients were treated with subpectoral Sentiva 1000 (Livanova PLC) insertion with axillary access by a neurosurgeon and a pediatric surgeon. The operative time was slightly longer compared to the traditional subcutaneous implant. All generators reported impedances within the optimal range. Blood loss was not significant and no other perioperative complications were reported. Patients and families were highly satisfied with the outcomes in terms of comfort and aesthetic results after surgery and at the last follow-up. No cases of infection occurred, and no malfunctions or displacements of the generator were registered at clinical follow-up., Conclusion: The transaxillary subpectoral placement of theVNS generator is an aesthetic and anatomic approach, which provides several benefits to children and young adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is used for treating depression but the efficacy and safety have not been well assessed. This study was conducted to evaluate the efficacy and safety of taVNS in depression., Methods: The retrieval databases included English databases of PubMed, Web of Science, Embase, the Cochrane Library and PsycINFO, and Chinese databases of CNKI, Wanfang, VIP and Sino Med, and the retrieval period was from their inception to November 10, 2022. The clinical trial registers (ClinicalTrials.gov and Chinese Clinical Trial Registry) were also searched. Standardized mean difference and the risk ratio were used as the effect indicator and the effect size was represented by the 95 % confidence interval. Revised Cochrane risk-of-bias tool for randomized trials and the Grades of Recommendation, Assessment, Development and Evaluation system were used to assess the risk of bias and quality of evidence respectively., Results: Totally, 12 studies of 838 participants were included. taVNS could significantly improve depression and reduce Hamilton Depression Scale scores. Low to very low evidence showed that taVNS had higher response rates than sham-taVMS and comparable response rates compared to antidepressants (ATD) and that taVNS combined with ATD had comparable efficacy to ATD with fewer side effects., Limitations: The number of studies in subgroups was small and the evidence quality was low to very low., Conclusions: taVNS is an effective and safe method for alleviating depression scores and had a comparable response rate to ATD., Competing Interests: Declaration of competing interest No conflict of interest exists in the submission of this manuscript., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Dysregulation of stress-reactive neuroendocrine measures, as well as subjective stress, have been found to worsen epilepsy. Transcutaneous vagus nerve stimulation (tVNS) is a relatively new treatment option for epilepsy. We were interested in its effect on the activity of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) as well as subjective stress and tiredness in patients with temporal lobe epilepsy (TLE)., Methods: Twenty patients (age 44 ± 11 years, 13 women) were enrolled in the study. They were free of seizures for more than 1 year. All took part in two sessions with 4 h of stimulation (tVNS vs. sham) in a randomized order. Saliva samples and subjective stress and tiredness levels were measured at five time points each session (before and after stimulation and three time points every hour in between). Data were analyzed using repeated measures analysis of variance as well as paired t-tests., Results: There was a dampened salivary cortisol (sCort) decrease during tVNS (time × condition effect: F [2.38, 38.15]  = 6.50, P = 0.002, partial η 2  = 0.29). Furthermore, we detected a dampened increase in salivary flow rate during tVNS (time × condition effect: F [3.28, 55.67]  = 2.82, P = 0.043, partial η 2  = 0.14). There was neither a difference in overall sCort or salivary alpha-amylase (sAA) levels nor in subjective stress or tiredness levels between conditions. sAA levels at the last measurement point were slightly higher during tVNS (t (19)  = 2.26, P = 0.035, d = 0.51), but this effect failed to reach significance when controlled for multiple comparisons., Significance: Our results partially support that tVNS influences the regulation of stress-reactive neuroendocrine systems (namely the HPA axis and ANS) in epilepsy. More research with larger samples is needed on the difference between short-term and repeated long-term stimulation., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Vagus nerve stimulation (VNS) has gained enormous traction as a promising bioelectronic therapy. In particular, the delivery of VNS paired with training to promote neural changes has demonstrated clinical success for stroke recovery and found far-reaching application in other domains, from autism to psychiatric disorders to normal learning. The success of paired VNS has been extensively documented. Here, we consider a more unusual question: why does VNS have such broad utility, and perhaps more importantly, when does VNS not work? We present a discussion of the concepts that underlie VNS therapy and an anthology of studies that describe conditions in which these concepts are violated and VNS fails. We focus specifically on the mechanisms engaged by implanted VNS, and how the parameters of stimulation, stimulation method, pharmacological manipulations, accompanying comorbidities, and specifics of concurrent training interact with these mechanisms to impact the efficacy of VNS therapy. As paired VNS therapy is increasing translated to clinical implementation, a clear understanding of the conditions in which it does, and critically, does not work is fundamental to the success of this approach., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MPK has a financial interest in MicroTransponder, Inc., which is developing VNS for stroke. RLR is founder and CEO of Xnerve, Inc., which is developing neurostimulation technologies. SAH has no conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We previously found that vagus nerve stimulation (VNS) strengthened stimulus-evoked activity in the superficial layer of the sensory cortex but not in the deep layer, suggesting that VNS altered the balance between the feedforward (FF) and feedback (FB) pathways. Band-specific oscillatory activities in the cortex could serve as an index of the FF-FB balance, but whether VNS affects cortical oscillations along sensory pathways through neuromodulators remains unclear., Hypothesis: VNS modulates the FF-FB balance through the cholinergic and noradrenergic systems, which modulate stimulus gain in the cortex., Methods: We investigated the effects of VNS using electrocorticography in the auditory cortex of 34 Wistar rats under general anesthesia while presenting click stimuli. In the time-frequency analyses, the putative modulation of the FF and FB pathways was estimated using high- and low-frequency power. We assessed, using analysis of variance, how VNS modulates auditory-evoked activities and how the modulation changes with cholinergic and noradrenergic antagonists., Results: VNS increased auditory cortical evoked potentials, consistent with results of our previous work. Furthermore, VNS increased auditory-evoked gamma and beta powers and decreased theta power. Local administration of cholinergic antagonists in the auditory cortex selectively disrupted the VNS-induced increase in gamma and beta power, while noradrenergic antagonists disrupted the decrease in theta power., Conclusions: VNS might strengthen the FF pathway through the cholinergic system and attenuate the FB pathway through the noradrenergic system in the auditory cortex. Cortical gain modulation through the VNS-induced neuromodulatory system provides new mechanistic insights into the effect of VNS on auditory processing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

As cardiac vagal control is a hallmark of good health and self-regulatory capacity, researchers are seeking ways to increase vagally mediated heart rate variability (vmHRV) in an accessible and non-invasive way. Findings with transcutaneous auricular vagus nerve stimulation (taVNS) have been disappointing in this respect, as its effects on vmHRV are inconsistent at best. It has been speculated that combining taVNS with other established ways to increase vmHRV may produce synergistic effects. To test this idea, the present study combined taVNS with slow breathing in a cross-over design. A total of 22 participants took part in two sessions of breathing at 6 breaths/min: once combined with taVNS, and once combined with sham stimulation. Electrical stimulation (100 Hz, 400 µs) was applied during expiration, either to the tragus and cavum conchae (taVNS) or to the earlobe (sham). ECG was recorded during baseline, 20-minutes of stimulation, and the recovery period. Frequentist and Bayesian analyses showed no effect of taVNS (in comparison to sham stimulation) on the root mean square of successive differences between normal heartbeats, mean inter-beat interval, or spectral power of heart rate variability at a breathing frequency of 0.1 Hz. These findings suggest that expiratory-gated taVNS combined with the stimulation parameters examined here does not produce acute effects on vmHRV during slow breathing., (© 2023. The Author(s).)

Current research in brain stimulation suggests transcutaneous auricular vagus nerve stimulation (taVNS) as a promising tool to modulate cognitive functions in healthy populations, such as attention, memory, and executive functions. Empirical evidence in single-task contexts, suggests that taVNS promotes holistic task processing, which strengthens the integration of multiple stimulus features in task processing. However, it is unclear how taVNS might affect performance in multitasking, where the integration of multiple stimuli leads to an overlap in stimulus response translation processes, increasing the risk of between-task interference (crosstalk). In a single-blinded, sham-controlled, within-subject design, participants underwent taVNS while performing a dual task. To assess the effects of taVNS, behavioral (reaction times), physiological (heart rate variability, salivary alpha-amylase), and subjective psychological variables (e.g., arousal) were recorded over three cognitive test blocks. Our results revealed no overall significant effect of taVNS on physiological and subjective psychological variables. However, the results showed a significant increase in between-task interference under taVNS in the first test block, but not in the subsequent test blocks. Our findings therefore suggest that taVNS increased integrative processing of both tasks early during active stimulation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Over 55 million adults are living with dementia globally, which is projected to reach 157 million by 2050. Mild cognitive impairment (MCI), a syndrome of memory impairment with intact activities of daily living, may precede dementia by several years. Around 5-15% of individuals with MCI convert to dementia annually. Novel treatments which delay progression of MCI to dementia are urgently needed. Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive neuromodulation technique that targets the vagus nerve. Importantly, tVNS has been shown to improve cognition in healthy volunteers, but has not been extensively examined as a potential therapeutic approach in MCI. VINCI-AD will examine the safety and feasibility of tVNS in older adults with MCI., Design: VINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 participants with amnestic MCI. All participants will attend for three consecutive study visits during which they will be randomised to receive no stimulation (baseline), active tVNS stimulation (stimulation at cymba conchae of left ear) or sham tVNS stimulation (at earlobe). Safety will be primarily assessed by ascertainment of adverse events. Further safety assessment will examine the impact of acute tVNS on subjective (orthostatic symptoms), peripheral (finometry-based blood pressure) and central (assessed via Near Infrared Spectroscopy [NIRS]) haemodynamic responses to active stand. Feasibility will be determined using a custom-designed occupational assessment of device usability. Exploratory secondary analysis in VINCI-AD will examine the potential impact of acute tVNS on associative memory, spatial memory and inhibitory control to inform sample size estimates for future trials of tVNS in older adults with MCI., Discussion: VINCI-AD will report on the safety (adverse events/haemodynamic responses to active stand) and feasibility of tVNS as a potential therapeutic option in MCI. Detailed reporting of study eligibility and completion rates will be reported. Exploratory analysis will examine the potential cognitive benefits of acute tVNS on cognitive function in MCI to report potential effect sizes that may inform future clinical trials in this cohort., Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05514756 . Trial Registration Number NCT05514756 (24th August 2022 for this protocol, version 1.0.)., (© 2023. The Author(s).)

Vagus Nerve Stimulation (VNS) therapy is widely understood to provide clinically meaningful improvements in seizure control to patients with drug-resistant epilepsy, and has been a staple in the clinical armamentaria available to epileptologists for over 25 years. Despite the long history of evidence-based reviews by neurology professional societies, there is still evidence of a practice gap in VNS titration and dosing that aims to maximize clinical benefit. Recent retrospective analyses have strongly argued for a more consistent application of a population-wide target dose of VNS, and further argued the importance of quickly achieving this target dose to hasten the onset of clinical benefits; however, these analyses failed to provide evidence for practical implementation. Herein, we describe a randomized controlled trial assessing the impact of titrating VNS according to three different protocols to achieve the target dose of 1.5 mA at 500µsec, for a 20-Hz signal frequency. The study was registered as NCT02385526 on March 11, 2015. Sixty-two patients were randomized into treatment groups that followed different titration protocols. One protocol (Group A) was designed to align with currently accepted professional guidance for VNS titration and the manufacturer's labeling for VNS in epilepsy (Heck et al., 2002), while the other two protocols were derived from VNS applications in other therapeutic areas. Group A participants were most likely to achieve the target dose parameters in 12 weeks or less (81.8%), with a median time-until-achievement of the target dose of 8.1 weeks, while less than 60% of patients in other groups were able to achieve the same endpoint. Participants in all groups experienced low levels of transient tolerability concerns and adverse events, suggesting titration to the target dose in 12 weeks or less following the Group A protocol is generally acceptable to most patients. These findings indicate that patients receiving VNS for epilepsy can achieve the manufacturer-recommended dose range in 12 weeks or less. A wider implementation of the approach will likely improve the clinical impact of VNS on seizure control and prevent undertreatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AB currently receives clinical research funding from LivaNova USA Inc. for participation in the CORE-VNS Registry as a principal investigator. RV is an employee of LivaNova USA Inc. and holds stock or stock options. SB is a scientific consultant and serves on the speakers’ bureau for LivaNova USA, Inc. PA has no conflicts of interest to report. LivaNova USA Inc. is the manufacturer of the VNS Therapy System and was the sponsor of the ASCEND study. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Transauricular vagus nerve stimulation (taVNS) is being studied as a feasible intervention for stroke, but the mechanisms by which this non-invasive technique acts in the cortex are still broadly unknown., Objectives: This study aimed to systematically review the current pre-clinical evidence in the auricular vagus nerve stimulation (aVNS) neuroplastic effects in stroke., Methods: We searched, in December of 2022, in Medline, Cochrane, Embase, and Lilacs databases. The authors executed the extraction of the data on Excel. The risk of bias was evaluated by adapted Cochrane Collaboration's tool for animal studies (SYRCLES's RoB tool)., Results: A total of 8 studies published between 2015 and 2022 were included in this review, including 391 animal models. In general, aVNS demonstrated a reduction in neurological deficits (SMD = -1.97, 95% CI -2.57 to -1.36, I 2  = 44%), in time to perform the adhesive removal test (SMD = -2.26, 95% CI -4.45 to -0.08, I 2  = 81%), and infarct size (SMD = -1.51, 95% CI -2.42 to -0.60, I 2  = 58%). Regarding the neuroplasticity markers, aVNS showed to increase microcapillary density, CD31 proliferation, and BDNF protein levels and RNA expression., Conclusions: The studies analyzed show a trend of results that demonstrate a significant effect of the auricular vagal nerve stimulation in stroke animal models. Although the aggregated results show high heterogeneity and high risk of bias. More studies are needed to create solid conclusions.

Introduction: Literature on outcomes of patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive vagus nerve stimulation (VNS) lacks information on seizure types and the time course of therapeutic effects. We have therefore performed what is to our knowledge the largest and most in-depth analysis of the effectiveness of VNS in LGS patients paying special attention to the impact of VNS Therapy on individual seizure types., Methods: The VNS Therapy Outcomes Registry includes over 7000 patients. A propensity score matching method was employed to match patients with LGS to non-LGS patients with drug-resistant epilepsy (DRE). Overall seizure frequencies were assessed prior to implantation and at 3-, 6-, 12-, 18-, and 24-month follow-ups to derive the main study outcomes: response rates and time to first response., Results: A total of 564 LGS patients with sufficient data were identified in the registry and matched 2:1 to 1128 non-LGS patients. Responder rates at 24 months were 57.5% in the LGS group and 61.5% in the non-LGS group. Median seizure frequency reduction at 24 months was 64.3% versus 66.7% in the LGS versus non-LGS group, respectively. In both groups, VNS was most effective at reducing focal aware seizures, "other" seizures, generalized-onset non-motor seizures, and drop attacks with relative reduction rates for these seizure types at 24 months exceeding 90% in both groups. Time-to-first response did not differ between the groups; however, there was a significantly higher proportion of patients who regressed from bilateral tonic-clonic (BTC) seizure response in the LGS group versus the non-LGS group at 24 months: 22.4% versus 6.7%; p = .015., Conclusions: Although limited by its retrospective design, the study shows that the effectiveness of VNS is comparable in DRE patients with and without LGS; however, LGS patients may be more prone to fluctuating control of BTCs., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

A vagus nerve stimulation (VNS) device delivers electrical pulses to the vagus nerve at a rhythm defined by the duty cycle. The standard therapeutic range is advocated for an output current of 1.5-2.25 mA and a duty cycle of 10%. As the optimal settings vary from patient to patient, some patients may benefit from additional seizure reduction when stimulated beyond the standard range. A total of 74 patients (15 children aged <12 years and 59 adolescents/adults) who underwent VNS implantation between 2011 and 2020 and who were followed up for at least 2 years were included in this retrospective study. Stimulation parameters exceeding 2.25 mA of output current, 25% of duty cycle, and 0.5625 (2.25 mA × 25%) of current × duty cycle were defined as high stimulation. The proportion achieved an additional seizure reduction of 20%, and the 50% seizure reduction rate at the last follow-up was compared between adolescents/adults and children. Approximately 40% of patients in adolescents/adults treated with high stimulation experienced an additional acute effect, resulting in a 50% or greater reduction in seizures in almost all patients. Moreover, in adolescents/adults, 22.2%-41.9% of the patients were treated with high stimulation, and the responder rate was 69.5%. Conversely, the responder rate in children was 26.7%, significantly worse than that in adolescents/adults, despite higher stimulation. VNS with high-stimulation settings is effective for adolescent and adult patients with intractable epilepsy. Even high stimulation may not be effective in extremely refractory pediatric epilepsy with a high seizure frequency.

Objective . Vagus nerve stimulation (VNS), which involves a surgical procedure to place electrodes directly on the vagus nerve (VN), is approved clinically for the treatment of epilepsy, depression, and to facilitate rehabilitation in stroke. VNS at surgically implanted electrodes is often limited by activation of motor nerve fibers near and within the VN that cause neck muscle contraction. In this study we investigated endovascular VNS that may allow activation of the VN at locations where the motor nerve fibers are not localized. Approach . We used endovascular electrodes within the nearby internal jugular vein (IJV) to electrically stimulate the VN while recording VN compound action potentials (CAPs) and neck muscle motor evoked potentials (MEPs) in an acute intraoperative swine experiment. Main Results . We show that the stimulation electrode position within the IJV is critical for efficient activation of the VN. We also demonstrate use of fluoroscopy (cone beam CT mode) and ultrasound to determine the position of the endovascular stimulation electrode with respect to the VN and IJV. At the most effective endovascular stimulation locations tested, thresholds for VN activation were several times higher than direct stimulation of the nerve using a cuff electrode; however, this work demonstrates the feasibility of VNS with endovascular electrodes and provides tools to optimize endovascular electrode positions for VNS. Significance . This work lays the foundation to develop endovascular VNS strategies to stimulate at VN locations that would be otherwise too invasive and at VN locations where structures such as motor nerve fibers do not exist., (© 2023 IOP Publishing Ltd.)

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has been introduced as a non-invasive alternative to invasive vagus nerve stimulation (iVNS). While iVNS paired with tones has been highlighted as a potential effective therapy for the treatment of auditory disorders such as tinnitus, there is still scarce data available confirming the efficacy of non-invasive taVNS. Here, we assessed the effect of taVNS paired with acoustic stimuli on sensory-related electrophysiological responses., Methods: A total of 22 healthy participants were investigated with a taVNS tone-pairing paradigm using a within-subjects design. In a single session pure tones paired with either active taVNS or sham taVNS were repeatedly presented. Novel tones without electrical stimulation served as control condition. Auditory event related potentials and auditory cortex oscillations were compared before and after the tone pairing procedure between stimulation conditions., Results: From pre to post pairing, we observed a decrease in the N1 amplitude and in theta power to tones paired with sham taVNS while these electrophysiological measures remained stable for tones paired with active taVNS a pattern mirroring auditory sensory processing of novel, unpaired control tones., Conclusion: Our results demonstrate the efficacy of a short-term application of non-invasive taVNS to modulate auditory processing in healthy individuals and, thereby, have potential implications for interventions in auditory processing deficits., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. This study assessed the effectiveness of non-invasive vagus nerve stimulation (nVNS) in reducing brain lesion volume and improving neurobehavioral performance in a rat model of TBI. Animals were randomized into three experimental groups: (1) TBI with sham stimulation treatment (Control), (2) TBI treated with five lower doses (2-min) nVNS, and (3) TBI treated with five higher doses (2 × 2-min) nVNS. We used the gammaCore nVNS device to deliver stimulations. Magnetic resonance imaging studies were performed 1 and 7 days post-injury to confirm lesion volume. We observed smaller brain lesion volume in the lower dose nVNS group compared with the control group on days 1 and 7. The lesion volume for the higher dose nVNS group was significantly smaller than either the lower dose nVNS or the control groups on days 1 and 7 post-injury. The apparent diffusion coefficient differences between the ipsilateral and contralateral hemispheres on day 1 were significantly smaller for the higher dose (2 × 2 min) nVNS group than for the control group. Voxel-based morphometry analysis revealed an increase in the ipsilateral cortical volume in the control group caused by tissue deformation and swelling. On day 1, these abnormal volume changes were 13% and 55% smaller in the lower dose and higher dose nVNS groups, respectively, compared with the control group. By day 7, nVNS dampened cortical volume loss by 35% and 89% in the lower dose and higher dose nVNS groups, respectively, compared with the control group. Rotarod, beam walking, and anxiety performances were significantly improved in the higher-dose nVNS group on day 1 compared with the control group. The anxiety indices were also improved on day 7 post-injury compared with the control and the lower-dose nVNS groups. In conclusion, the higher dose nVNS (five 2 × 2-min stimulations) reduced brain lesion volume to a level that further refined the role of nVNS therapy for the acute treatment of TBI. Should nVNS prove effective in additional pre-clinical TBI models and later in clinical settings, it would have an enormous impact on the clinical practice of TBI in both civilian and military settings, as it can easily be adopted into routine clinical practice.

Background: Implanted vagus nerve stimulation (VNS) and transcutaneous auricular VNS (taVNS) have been primarily administered clinically to the unilateral-left vagus nerve. This left-only convention has proved clinically beneficial in brain disorders. However, in stroke survivors, the presence of a lesion in the brain may complicate VNS-mediated signaling, and it is important to understand the laterality effects of VNS in stroke survivors to optimize the intervention., Objective: To understand whether taVNS delivered to different ear targets relative to the lesion (ipsilesional vs contralesional vs bilateral vs sham) impacts blood oxygenation level dependent (BOLD) signal propagation in stroke survivors., Methods: We enrolled 20 adults with a prior history of stroke. Each participant underwent a single visit, during which taVNS was delivered concurrently during functional magnetic resonance imaging (fMRI) acquisition. Each participant received three discrete active stimulation conditions (ipsilesional, contralesional, bilateral) and one sham condition in a randomized order. Stimulation-related BOLD signal changes in the active conditions were compared to sham conditions to understand the interaction taVNS and laterality effects., Results: All active taVNS conditions deactivated the contralesional default mode network related regions compared to sham, however only ipsilesional taVNS enhanced the activations in the ipsilesional visuomotor and secondary visual cortex. Furthermore, we reveal an interaction in task activations between taVNS and cortical visuomotor areas, where ipsilesional taVNS significantly increased ipsilesional visuomotor activity and decreased contralesional visuomotor activity compared to sham., Conclusion: Laterality of taVNS relative to the lesion is a critical factor in optimizing taVNS in a stroke population, with ipsilesional stimulation providing largest direct brain activation and should be explored further when designing taVNS studies in neurorehabilitation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Vagus nerve stimulation (VNS) has the potential to treat various peripheral dysfunctions, but the traditional cuff electrodes for VNS are susceptible to off-target effects. Microelectrodes may enable highly selective VNS that can mitigate off-target effects, but they suffer from the increased impedance. Recent studies on microelectrodes with non-Euclidean geometries have reported higher energy efficiency in neural stimulation applications. These previous studies use electrodes with mm/cm-scale dimensions, mostly targeted for myelinated fibers. This study evaluates fractal microelectrodes for VNS in a rodent model (N = 3). A thin-film device with fractal and circle microelectrodes is fabricated to compare their neural stimulation performance on the same radial coordinate of the nerve. The results show that fractal microelectrodes can activate C-fibers with up to 52% less energy (p = 0.012) compared to circle microelectrodes. To the best of the knowledge, this work is the first to demonstrate a geometric advantage of fractal microelectrodes for VNS in vivo., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive method of brain stimulation that has been investigated for its use in the clinical treatment of a number of different conditions. There has been little investigation into the stimulation current that is delivered and the effect on individual variability in response to tVNS.Seventeen participants underwent tVNS, and stimulation current was determined based on individual pain threshold. To investigate individual variability, brain dynamics were measured concurrently using magnetoencephalography (MEG) in response to two different stimulation protocols of tVNS. The first protocol consisted of a sequence of equally spaced short (1ms) stimulation pulses applied 24 times per second (24 Hz), and the second consisted of a sequence of 24 pulses per second spaced according to a 6 Hz pulse frequency modulation (PFM). Both stimulation sequences were delivered to the cymba concha in the left ear.The difference in brain responses to the two sequences was initially calculated using a one-sample t-test at the group level, based on z-scoring of the data at the individual level, and no statistically significant differences were observed. Further investigation of individual variability suggested that participants fell into two groups; one that responded more strongly to 24 Hz and one that responded more strongly to the irregular spacing of pulses in the PFM protocol.We tested whether the stimulation current that the participant received could predict how they would respond to the stimulation, but we did not observe any correlation. This supports the literature that suggests that selecting stimulation current based on individual pain threshold is a suitable procedure for tVNS, and higher stimulation intensities does not correspond to stronger brain response. Further investigation into individual variability in response to different frequencies and pulse spacing of tVNS should also be investigated further and may lead to the development of personalised stimulation protocols.Clinical relevance- The stimulation current at which tVNS is delivered does not appear to influence brain response to stimulation, and the value of stimulation current should be selected based on individual participant comfort.

Introduction: Following approval in 2009 of vagus nerve stimulation (VNS Therapy) for drug-resistant epilepsy (DRE) in the Russian Federation, this is the first multicenter study across Russia to evaluate the safety and efficacy of adjunctive VNS Therapy., Methods: The retrospective, observational registry included 58 pediatric patients with DRE (5-17 years old at implantation) who had ≥2 years of VNS. To ensure a robust evaluation process, changes in seizure frequency were evaluated for all seizure types as well as "most disabling" seizures (defined as seizures accompanied by falls, physical trauma, and/or incontinence in the absence of preventative measures)., Results: With 2 years of VNS Therapy, 37 of 49 patients (76%) experiencing the most disabling epileptic seizures had a >50% decrease in frequency of such seizures, and 16 (33%) reported no longer experiencing the "most disabling" seizure type. In addition, based on the McHugh Outcome scale, VNS Therapy had a positive outcome on both frequency and severity of all epileptic seizure types, with a >50% decrease in frequency of all epileptic seizure types noted in 37 of 58 patients (64%), and 31% of patients had a Class I outcome, including 11 patients (19%) who achieved seizure freedom. VNS Therapy also had a positive effect on the frequency of status epilepticus: 13 patients (22%) had status epilepticus prior to implantation with a mean rate of 9.4 ± 17.7 events per year (range, 0-52), and after VNS Therapy, only one patient continued to experience status epilepticus (at 1 event per 4-6 months). VNS Therapy had an acceptable safety profile and no adverse events leading to VNS discontinuation were reported., Conclusions: The results demonstrate that VNS Therapy is being safely and effectively applied to pediatric patients in the Russian healthcare system., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Objective. We demonstrated how automated simulations to characterize electrical nerve thresholds, a recently published open-source software for modeling stimulation of peripheral nerves, can be applied to simulate accurately nerve responses to electrical stimulation. Approach. We simulated vagus nerve stimulation (VNS) for humans, pigs, and rats. We informed our models using histology from sample-specific or representative nerves, device design features (i.e. cuff, waveform), published material and tissue conductivities, and realistic fiber models. Main results. Despite large differences in nerve size, cuff geometry, and stimulation waveform, the models predicted accurate activation thresholds across species and myelinated fiber types. However, our C fiber model thresholds overestimated thresholds across pulse widths, suggesting that improved models of unmyelinated nerve fibers are needed. Our models of human VNS yielded accurate thresholds to activate laryngeal motor fibers and captured the inter-individual variability for both acute and chronic implants. For B fibers, our small-diameter fiber model underestimated threshold and saturation for pulse widths >0.25 ms. Our models of pig VNS consistently captured the range of in vivo thresholds across all measured nerve and physiological responses (i.e. heart rate, A δ /B fibers, A γ fibers, electromyography, and A α fibers). In rats, our smallest diameter myelinated fibers accurately predicted fast fiber thresholds across short and intermediate pulse widths; slow unmyelinated fiber thresholds overestimated thresholds across shorter pulse widths, but there was overlap for pulse widths >0.3 ms. Significance. We elevated standards for models of peripheral nerve stimulation in populations of models across species, which enabled us to model accurately nerve responses, demonstrate that individual-specific differences in nerve morphology produce variability in neural and physiological responses, and predict mechanisms of VNS therapeutic and side effects., (© 2023 IOP Publishing Ltd.)

Perseverative cognitions can provoke psychophysiological stress in the absence of an actual stressor and are considered important transdiagnostic vulnerability factors for several (mental) health issues. These stress-related cognitive processes are reflected by both cognitive (assessed by self-reports) and autonomic inflexibility (assessed by heart rate variability; HRV), with a key role attributed to the vagus nerve. Interestingly, modulation of the afferent branches of the vagus can be achieved with transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive technique that employs a low-intensity electrical current applied to the ear. In a sample of healthy individuals, we investigated the effects of taVNS of the left concha, compared to sham (earlobe) stimulation, on the cognitive and autonomic correlates of perseverative cognition following a psychosocial stress task. Interestingly, taVNS significantly reduced cognitive rigidity, reflected by reduced subjective perseverative thinking after psychosocial stress. Although there were no direct effects on autonomic correlates of perseverative cognition, individual differences in perseverative thinking after the stressor significantly affected the effects of taVNS on HRV. Specifically, more autonomic inflexibility during the stress task (i.e., reduced HRV) was associated with increases in perseverative thinking afterward for the sham condition, but not the active taVNS condition. Additional exploratory analyses revealed no significant moderation of stimulation intensity. Overall, the study findings endorse the association between perseverative cognitions and vagus nerve functioning., (© 2023 Society for Psychophysiological Research.)

Background: Implanted vagus nerve stimulation (VNS), when synchronized with post-stroke motor rehabilitation improves conventional motor rehabilitation training. A non-invasive VNS method known as transcutaneous auricular vagus nerves stimulation (taVNS) has emerged, which may mimic the effects of implanted VNS., Objective: To determine whether taVNS paired with motor rehabilitation improves post-stroke motor function, and whether synchronization with movement and amount of stimulation is critical to outcomes., Methods: We developed a closed-loop taVNS system for motor rehabilitation called motor activated auricular vagus nerve stimulation (MAAVNS) and conducted a randomized, double-blind, pilot trial investigating the use of MAAVNS to improve upper limb function in 20 stroke survivors. Participants attended 12 rehabilitation sessions over 4-weeks, and were assigned to a group that received either MAAVNS or active unpaired taVNS concurrently with task-specific training. Motor assessments were conducted at baseline, and weekly during rehabilitation training. Stimulation pulses were counted for both groups., Results: A total of 16 individuals completed the trial, and both MAAVNS (n = 9) and unpaired taVNS (n = 7) demonstrated improved Fugl-Meyer Assessment upper extremity scores (Mean ± SEM, MAAVNS: 5.00 ± 1.02, unpaired taVNS: 3.14 ± 0.63). MAAVNS demonstrated greater effect size (Cohen's d  = 0.63) compared to unpaired taVNS (Cohen's d  = 0.30). Furthermore, MAAVNS participants received significantly fewer stimulation pulses (Mean ± SEM, MAAVNS: 36 070 ± 3205) than the fixed 45 000 pulses unpaired taVNS participants received ( P  < .05)., Conclusion: This trial suggests stimulation timing likely matters, and that pairing taVNS with movements may be superior to an unpaired approach. Additionally, MAAVNS effect size is comparable to that of the implanted VNS approach.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of childbearing age. The etiology of PCOS is multifactorial, and current treatments for PCOS are far from satisfactory. Recently, an imbalanced autonomic nervous system (ANS) with sympathetic hyperactivity and reduced parasympathetic nerve activity (vagal tone) has aroused increasing attention in the pathogenesis of PCOS. In this paper, we review an innovative therapy for the treatment of PCOS and related co-morbidities by targeting parasympathetic modulation based on non-invasive transcutaneous auricular vagal nerve stimulation (ta-VNS). In this work, we present the role of the ANS in the development of PCOS and describe a large number of experimental and clinical reports that support the favorable effects of VNS/ta-VNS in treating a variety of symptoms, including obesity, insulin resistance, type 2 diabetes mellitus, inflammation, microbiome dysregulation, cardiovascular disease, and depression, all of which are also commonly present in PCOS patients. We propose a model focusing on ta-VNS that may treat PCOS by (1) regulating energy metabolism via bidirectional vagal signaling; (2) reversing insulin resistance via its antidiabetic effect; (3) activating anti-inflammatory pathways; (4) restoring homeostasis of the microbiota-gut-brain axis; (5) restoring the sympatho-vagal balance to improve CVD outcomes; (6) and modulating mental disorders. ta-VNS is a safe clinical procedure and it might be a promising new treatment approach for PCOS, or at least a supplementary treatment for current therapeutics., (© 2023. The Author(s).)