Vagus nerve stimulation in cerebral stroke:biological mechanisms,therapeutic modalities,clinical applications,and future directions

Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life.Many stro ke victims are left with long-term neurological dysfunction,which adversely affects the well-being of the individual and the broader socioeconomic impact.Currently,poststroke brain dysfunction is a major and difficult area of treatment.Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autis m,refractory depression,epilepsy,and Alzheimer’s disease.It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as alte ring neurotransmitters and the plasticity of central neuro ns.In animal models of acute ischemic stroke,vagus nerve stimulation has been shown to reduce infarct size,reduce post-stroke neurological damage,and improve learning and memory capacity in rats with stroke by reducing the inflammatory response,regulating bloodbrain barrier permeability,and promoting angiogenesis and neurogenesis.At present,vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation.Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in im proving upper limb motor and cognitive abilities in stroke patients.Further clinical studies have shown that non-invasive vagus nerve stimulation,including ear/ce rvical vagus nerve stimulation,can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect.In this paper,we first describe the multiple effects of vagus nerve stimulation in stroke,and then discuss in depth its neuroprotective mechanisms in ischemic stroke.We go on to outline the res ults of the current major clinical applications of invasive and non-invasive vagus nerve stimulation.Finally,we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends.We believe that vagus nerve stimulation,as an effective treatment for stroke,will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability.

Vagus nerve stimulation is a potential treatment for ischemic stroke

Microglia are the brain’s primary innate immune cells,and they are activated and affect pro-inflammatory phenotype or regulatory phenotype after ischemic stroke.Vagus nerve stimulation was shown to activate microglial phenotypic changes and exhibit neuroprotective effects in ischemia/reperfusion injury.In this study,we established rat models of ischemic stroke by occlusion of the middle cerebral artery and performed vagus nerve stimulation 30 minutes after modeling.We found that vagus nerve stimulation caused a shift from a pro-inflammatory phenotype to a regulatory phenotype in microglia in the ischemic penumbra.Vagus nerve stimulation decreased the levels of pro-inflammatory phenotype markers inducible nitric oxide synthase and tumor necrosis factorαand increased the expression of regulatory phenotype markers arginase 1 and transforming growth factorβthrough activatingα7 nicotinic acetylcholine receptor expression.Additionally,α7 nicotinic acetylcholine receptor blockade reduced the inhibition of Toll-like receptor 4/nuclear factor kappa-B pathwayassociated proteins,including Toll-like receptor 4,myeloid differentiation factor 88,I kappa B alpha,and phosphorylated-I kappa B alpha,and also weakened the neuroprotective effects of vagus nerve stimulation in ischemic stroke.Vagus nerve stimulation inhibited Toll-like receptor 4/nuclear factor kappa-B expression through activatingα7 nicotinic acetylcholine receptor and regulated microglial polarization after ischemic stroke,thereby playing a role in the treatment of ischemic stroke.Findings from this study confirm the mechanism underlying vagus nerve stimulation against ischemic stroke.

Vagus nerve stimulation protects against cerebral injury after cardiopulmonary resuscitation by inhibiting inflammation through the TLR4/NF-κB and α7nAChR/JAK2 signaling pathways

BACKGROUND: Our previous research proved that vagus nerve stimulation(VNS) improved the neurological outcome after cardiopulmonary resuscitation(CPR) by activating α7 nicotinic acetylcholine receptor(α7nAChR) in a rat model, but the underlying mechanism of VNS in neuroprotection after CPR remains unclear.METHODS: In vivo, we established a mouse model of cardiac arrest(CA)/CPR to observe the survival rate, and the changes in inflammatory factors and brain tissue after VNS treatment. In vitro, we examined the effects of α7nAChR agonist on ischemia/reperfusion(I/R)-induced inflammation in BV2 cells under oxygen-glucose deprivation/reoxygenation(OGD/R) conditions. We observed the changes in cell survival rate, the levels of inflammatory factors, and the expressions of α7nAChR/Janus kinase 2(JAK2) and toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB).RESULTS: In vivo, VNS preconditioning enhanced functional recovery, improved the survival rate, and reduced hippocampal CA1 cell damage, and the levels of inflammatory mediators after CA/CPR. The application of α7nAChR agonists provided similar effects against cerebral injury after the return of spontaneous circulation(ROSC), while α7nAChR antagonists reversed these neuroprotective impacts. The in vitro results mostly matched the findings in vivo. OGD/R increased the expression of tumor necrosis factor-alpha(TNF-α), TLR4 and NF-κB p65. When nicotine was added to the OGD/R model, the expression of TLR4, NF-κB p65, and TNF-α decreased, while the phosphorylation of JAK2 increased, which was prevented by preconditioning with α7nAChR or JAK2 antagonists.CONCLUSION: The neuroprotective effect of VNS correlated with the activation of α7nAChR. VNS may alleviate cerebral IR injury by inhibiting TLR4/NF-κB and activating the α7nAChR/JAK2 signaling pathway.

Advances of Research on Auricular Vagus Nerve Stimulation for Treatment of Nervous System Diseases

As a new type of nerve regulation technology, Vagus Nerve Stimulation is currently used in the treatment of nervous system diseases. Auricular Vagus Nerve Stimulation has become one of the research hotspots in this field, because there is no implantation risk. However, there is no unified standard for the treatment parameters of aVNS for nervous system diseases. In this paper, the research progress of the anatomical structure and parameters of the vagus nerve and its role in nervous system diseases are reviewed to provide basis for further research.

Electrical stimulation of the vagus nerve protects against cerebral ischemic injury through an anti-inflammatory mechanism

Vagus nerve stimulation exerts protective effects against ischemic brain injury; however, the underlying mechanisms remain unclear. In this study, a rat model of focal cerebral ischemia was established using the occlusion method, and the right vagus nerve was given electrical stimula-tion （constant current of 0.5 mA; pulse width, 0.5 ms; frequency, 20 Hz; duration, 30 seconds; every 5 minutes for a total of 60 minutes） 30 minutes, 12 hours, and 1, 2, 3, 7 and 14 days after surgery. Electrical stimulation of the vagus nerve substantially reduced infarct volume, improved neurological function, and decreased the expression levels of tumor necrosis factor-α and in-terleukin-6 in rats with focal cerebral ischemia. The experimental findings indicate that the neuroprotective effect of vagus nerve stimulation following cerebral ischemia may be associated with the inhibition of tumor necrosis factor-α and interleukin-6 expression.

Wake-promoting effects of vagus nerve stimulation after traumatic brain injury: upregulation of orexin-A and orexin receptor type 1 expression in the prefrontal cortex

Orexins, produced in the lateral hypothalamus, are important neuropeptides that participate in the sleep/wake cycle, and their expres- sion coincides with the projection area of the vagus nerve in the brain. Vagus nerve stimulation has been shown to decrease the amounts of daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury. In the present study, we investigated whether vagus nerve stimulation promotes wakefulness and affects orexin expression. A rat model of traumatic brain injury was established using the free fall drop method. In the stimulated group, rats with traumatic brain injury received vagus nerve stimulation （frequency, 30 Hz, current, 1.0 mA; pulse width, 0.5 ms; total stimulation time, 15 minutes）. In the antagonist group, rats with traumatic brain injury were intracerebroventricularly injected with the orexin receptor type 1 （OXIR） antagonist SB334867 and received vagus nerve stimulation. Changes in consciousness were observed after stimulation in each group. Enzyme-linked immunosorbent assay, western blot assay and immunohistochemistry were used to assess the levels of orexin-A and OX1R expression in the prefrontal cortex. In the stimulated group, consciousness was substantially improved, orexin-A protein expression gradually increased within 24 hours after injury and OX1R expres- sion reached a peak at 12 hours, compared with rats subjected to traumatic brain injury only. In the antagonist group, the wake-promoting effect of vagus nerve stimulation was diminished, and orexin-A and OX1R expression were decreased, compared with that of the stim- ulated group. Taken together, our findings suggest that vagus nerve stimulation promotes the recovery of consciousness in comatose rats after traumatic brain injury. The upregulation of orexin-A and OXIR expression in the prefrontal cortex might be involved in the wake-promoting effects of vagus nerve stimulation.

Neuroprotective effects of vagus nerve stimulation on traumatic brain injury

Previous studies have shown that vagus nerve stimulation can improve the prognosis of trau- matic brain injury. The aim of this study was to elucidate the mechanism of the neuroprotective effects of vagus nerve stimulation in rabbits with brain explosive injury. Rabbits with brain ex- plosive injury received continuous stimulation （10 V, 5 Hz, 5 ms, 20 minutes） of the right cervical vagus nerve. Tumor necrosis factor-a, interleukin-l~ and interleukin-10 concentrations were detected in serum and brain tissues, and water content in brain tissues was measured. Results showed that vagus nerve stimulation could reduce the degree of brain edema, decrease tumor necrosis factor-a and interleukin-1β concentrations, and increase interleukin-10 concentration after brain explosive injury in rabbits. These data suggest that vagus nerve stimulation may exert neuroprotective effects against explosive injury via regulating the expression of tumor necrosis factor-a, interleukin-1 β and interleukin-10 in the serum and brain tissue.

The mechanisms through which auricular vagus nerve stimulation protects against cerebral ischemia/reperfusion injury

Previous studies have shown that vagus nerve stimulation can improve patients' locomotor function.The stimulation of the auricular vagus nerve,which is the only superficial branch of the vagus nerve,may have similar effects to vagus nerve stimulation.However,the precise mechanisms remain poorly understood.In this study,rat models of cerebral ischemia/reperfusion injury were established by modified Longa ligation.Twenty-four hours later,7-day auricular vagus nerve stimulation was performed.The results showed that auricular vagus nerve stimulation promoted the secretion of acetylcholine,inhibited the secretion of interleukin-1β,interleukin-6,and tumor necrosis factor-α,and reduced connexin 43 phosphorylation in the ischemic penumbra and motor cortex,promoting locomotor function recovery in rats with cerebral ischemia/reperfusion injury.These findings suggested that auricular vagus nerve stimulation promotes the recovery of locomotor function in rats with cerebral ischemia/reperfusion injury by altering the secretion of acetylcholine and inflammatory factors and the phosphorylation of connexin 43.This study was approved by the Animal Use and Management Committee of Shanghai University of Traditional Chinese Medicine on November 8,2019(approval No.PZSHUTCM191108014).

Left-sided vagus nerve stimulation improves cardiopulmonary resuscitation outcomes in rats as effectively as right-sided vagus nerve stimulation

BACKGROUND: Our group previously reported that right-sided vagus nerve stimulation(RVNS) significantly improved outcomes after cardiopulmonary resuscitation(CPR) in a rat model of cardiac arrest(CA). However, whether left-sided vagus nerve stimulation(LVNS) could achieve the same effect as RVNS in CPR outcomes remains unknown.METHODS: A rat model of CA was established using modified percutaneous epicardial electrical stimulation to induce ventricular fibrillation(VF). Rats were treated with LVNS or RVNS for 30 minutes before the induction of VF. All animals were observed closely within 72 hours after return of spontaneous circulation(ROSC), and their health and behavior were evaluated every 24 hours.RESULTS: Compared with those in the RVNS group, the hemodynamic measurements in the LVNS group decreased more notably. Vagus nerve stimulation(VNS) decreased the serum levels of tumor necrosis factor-alpha(TNF-α) and the arrhythmia score, and attenuated inflammatory infiltration in myocardial tissue after ROSC, regardless of the side of stimulation, compared with findings in the CPR group. Both LVNS and RVNS ameliorated myocardial function and increased the expression of α-7 nicotinic acetylcholine receptor in the myocardium after ROSC. Moreover, a clear improvement in 72-hour survival was shown with VNS pre-treatment, with no significant difference in efficacy when comparing the laterality of stimulation. CONCLUSIONS: LVNS may have similar effects as RVNS on improving outcomes after CPR.

A review of studies on the therapeutic effect of vagus nerve stimulation

BACKGROUND： Vagus nerve widely innervates in the human body, and it has diverse physiological functions. Many new physiological functions are gradually found. Studies on its action mechanism have been gradually deepened. Vagus nerve stimulation （VNS） has been used for treatment of epilepsy and depression in clinic. OBJECTIVE： To retrospectively investigate the therapeutic effects and mechanism of VNS. RETRIEVE STRATEGY： A computer-based online research in Pubmed with the key words of ＂vagus nerve stimulation＂ published between February 1990 and October 2006 in English were systemically reviewed. Totally 583 articles were collected and primarily selected. Inclusive criteria： the mechanism of therapeutic effects of VNS-related literatures. Exclusive criteria： repetitive study. LITERATURE EVALUATION： According to inclusive criteria, of the 57 articles, which met the inclusive criteria, 42 were associated with the therapeutic function of VNS, and 15 with the mechanism of these related functions. DATA SYNTHESIS： Vagus nerve has special nerve innervation and wide projection with extensive physiological effects. Till now, VNS has been used in the therapy of epilepsy and depression, and exact clinical effects have been obtained. Further studies have discovered other functions of VNS, such as the effect on the memory power, cognition, and perception to pain. Thus, the studies about VNS become diverse. Just because of the special physiological functions of vagus nerve, VNS can bring some adverse reactions such as foreign body sensation, hoarseness, trigeminal neuralgia, etc. The mechanism of therapeutic function of VNS is still under exploration. CONCLUSION： As a mature surgical technique, VNS has been widely used in the therapy of epilepsy, depression, inflammation, analgesia, relieving itching, etc. Although the mechanism is still unclear, it brings obvious clinical effects.

Effects of vagus nerve stimulation on parafascicular nucleus neuronal activities in rats

BACKGROUND： Vagal nerve fibers have many projections to the central nervous system. The anti-epileptic effects of vagus nerve stimulation （VNS） are associated with the thalamus, insular cortex, and other brain regions. OBJECTIVE： To validate the inhibitory effects of vagus nerve stimulation on firing activities of parafascicular nucleus （Pf） neurons in rats. DESIGN, TIME, AND SETTING： The experiment was performed in the Electrophysiological Laboratory of Department of Neurobiology, Liaoning Medical University between September 2006 and September 2007 with multiple-factor self-controlled design. MATERIALS： Twenty-two healthy adult male Sprague Dawley rats were obtained for this experiment. Main instruments： A320R constant electrical stimulation was made by United States World Precision Instruments, Spike2 Biological Signal Processing Systems was provided by British CED Company. METHODS： Under general anesthesia, the left cervical vagus nerve of rats was separated by approximately 1.0 cm. A stimulation electrode was deployed on the vagus nerve, with various settings for VNS parameters. MAIN OUTCOME MEASURES： ① Firing rates of Pf before and after various VNS parameters were measured according to effect （R） ≥ 20%： excited effect, R ≤ -20%： inhibited effect, -20% 〈 R 〈 20%： no effect. ② Firing rates of excited Pf neurons after various VNS parameters were measured. RESULTS： ① One rat died prior to recording, another was recorded in the wrong brain location, but the remaining 20 rats were included in the final analysis. ② A total of 221 Pf neurons in healthy rats were recorded. The spontaneous firing rats were （6.70 ± 0.56） Hz and varied between 0.34-52.5 Hz. The spontaneous firing rates were significantly increased in 146 neurons （66.1%）, increasing from （5.36 ± 0.59） Hz to （8.22 ± 0.81） Hz （P 〈 0.01）. A total of 40 （18.1%） neurons did not respond, and 35 （15.8%） neurons were inhibited. ③ The excitation rates of Pf neurons did not increase with increasing current intensity from 3.0 mA to 5.0 mA. ④ When the current intensity was set to 3.0-4.0 mA, excitation rates of Pf neurons decreased with increasing stimulation frequency of 30 -50 Hz. The excitation ratios were not reduced by an intensity of 5.0 mA. CONCLUSION： VNS may result in excited Pf neurons that may inhibit cerebral cortical activities.

Young children with multidrug-resistant epilepsy and vagus nerve stimulation responding to perampanel: A case report

BACKGROUND Perampanel(PER),a third-generation antiepileptic drug,is a selective and noncompetitiveα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist,and has been approved for the treatment of adults and adolescents with focal epilepsy.However,there are only a few studies about the efficacy and tolerability of PER in young children with multidrug-resistant epilepsy.In this case,we aimed to share our clinical experience in this group.CASE SUMMARY A 4-year-old boy without perinatal asphyxia and familial history of epilepsy began to have ictal seizures from age 14 mo,with jerky movement of four limbs and head nodding.Abnormal multifocal discharge and background activity were recorded through electroencephalography,and no pathogenic mutation was found in the whole exome sequencing for the patient and his parents.He had received valproate,levetiracetam,topiramate,oxcarbazepine,clonazepam and lacosamide sequentially at different times,but he still had frequent seizures even after vagus nerve stimulation(VNS)implantation.He was diagnosed with idiopathic multidrug-resistant epilepsy.However,his seizure frequency was significantly reduced after PER administration in a dose-dependent manner,and better cognitive behavior was observed.In addition,the adverse reactions of anger and aggression also appeared.CONCLUSION PER is effective as add-on therapy for young children with multidrug-resistant epilepsy who have previously undergone VNS implantation.

GTCS-Vagus Nerve Stimulator Automation Using Private IoT-Blockchain Smartcontract

Generalized Tonic Clonic Seizure(GTCS)is a form of epileptic seizure in which a patient loses control over their entire body,ultimately leading to loss of consciousness.The Vagus Nerve Stimulator(VNS)is a tool/method for treating epileptic episodes that sends counter-electrical stimulations to the Vagus Nerve in order to mitigate epileptic signals from the brain.The machine is a stand-alone device that depends on human decision-making.The proposed framework uses an IoT and Blockchain oversight mechanism to augment the device's transparency.The system counteracts against false-activation by monitoring the patient's vitals through a smart watch and allows only legitimate use.The nominal operating threshold is determined by preprocessing inferences that include an 18-year-old GTCS epileptic patient and a data set of 281 non-GTCS epileptic patients.The proposed system functions as a dual control lock where the IoT system and the manually activation system work in tandem to activate the device.Based on the values sensed by the IoT device,the deployed system is able to make deci-sions and regulate the use of the VNS.The IoT-Blockchain framework is able to fully eradicate false activation by increasing accuracy and transparency,ensur-ing the device is used correctly and safely.

Research progress on the electrophysiological indicators to predict the efficacy of vagus nerve stimulation for drug-refractory epilepsy

Vagus nerve stimulation(VNS)is an important treatment option for drug-refractory epilepsy(DRE),with well-established efficacy and safety in clinical practice for more than 20 years.However,it is very difficult to find the optimal electrophysiological indicators for the effectiveness of VNS on DRE because the mechanism of action is unknown.In this review,we provide an update of the potential applications of VNS outcomes in patients with drug-resistant epilepsy.Electroencephalographic(EEG)activity,event-related potentials,EEG synchronization levels,magnetoencephalographic,laryngeal muscle evoked potentials,and heart rate variability are potential biomarkers for VNS outcomes in people with DRE.

Stimulation and Control of Homeostasis

Healthy homeostasis is a principal driving force of the dynamic equilibrium of living organisms. The dynamical basis of homeostasis is the complex and interconnected feedback mechanisms, which are fundamentally governed by the nervous system, mainly the balance of the sympathetic and parasympathetic controlling actions. The balancing regulation is well presented in the heart’s sinus node and can be measured by the time-domain heart-rate variation (HRV) of its frequency domain to analyze the constitutional frequencies of the variation. This last is a fluctuation that shows 1/f time fractal arrangement (f is the composing frequency). The time-fractal arrangement could depend on the structural fractal of the His-Purkinje system of the heart and personally modify the HRV. The cancers gradually destroy the homeostatic harmony, starting locally and finishing systemically. The controlling activity of vagus-nerve changes the HRV or the power density spectrum of the signal fluctuations in malignant development, presenting an appropriate control of the cancerous processes. The modified spectrum by a non-invasive radiofrequency treatment could arrest the tumor growth. An appropriate modulation could support the homeostatic control and force reconstructing of the broken complexity.

Auricular vagus nerve acupressure for patients with emotional distress under the COVID-19 pandemic:A smartphone-based,randomized controlled trial

Objective: To confirm whether self-administered AVNA treatment is effective in improving emotional distressunder the COVID-19 pandemic.Methods: A smartphone-based online, randomized, controlled trial was designed from 26 February 2020 to 28April 2020 in four study sites, including Wuhan, Beijing, Shenyang, and Guangzhou of China. Local residentswho had considerable emotional distress with a score of the Hospital Anxiety and Depression Scale (HADS) ≥9 were recruited. Participants were randomly assigned to three times of AVNA (n = 191) per day, in morning,around noon, and in evening or usual care (UC, n = 215) once daily for 14 days. The primary outcome was theresponse rate, which was the proportion of participants whose Hospital Anxiety and Depression Scale (HADS)score reduced from baseline by ≥ 50%. The assessment was conducted at baseline, 3 days, and 14 days.Results: The AVNA group had a markedly higher response rate than the UC group at 3 days (35.6% vs. 24.9%,P = 0.02) and at 14 days (70.7% vs. 60.6%, P = 0.02). The AVNA group showed significantly greater reductionin scores of HADS at the two measurement points and BAI at 3 days (P ≤ 0.03), with average respective effectsize of 0.217 and 0.195. Participants with AVNA spent less time falling asleep and rated their sleep qualitybeing remarkably higher than those with UC at endpoint.Conclusion: During COVID-19 pandemic period, treatment with self-administrated AVNA was more effectivethan UC in reducing emotional distress of isolated populations. These findings support self-administered AVNAas a treatment option for patients with emotional distress under the COVID-19 pandemic or other emergentevents.

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

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

Transcutaneous auricular vagus nerve stimulation would be an alternative to implantable cervical vagus nerve stimulation in some situation

Implantable cervical vagus nerve stimulation(i VNS) is a representative and promising neuromodulation.However,the invasive nature restricts its application.Traditional auricular acupuncture treatment has a long history.The auricular branch of the vagus nerve(ABVN) is a branch on the surface of the ear.Some studies demonstrates that transcutaneous auricular vagus nerve stimulation(ta VNS) would achieve similar effects as i VNS.Ta VNS and i VNS share a common anatomical basis and acting mechanism.In this article,we made a comparison between i VNS and ta VNS in indications and efficacy.The recent studies have revealed similar clinical efficacy of ta VNS,ta VNS would expand the indication of i VNS.Highquality clinical evidences are needed before ta VNS become be an alternative of i VNS.

A Review of the Surgical Procedures for the Treatment of Drug-Resistant Epilepsy and Their Seizure Control Outcomes

Background: Drug-resistant epilepsy can be defined as the existence of seizures within 6 months, despite adequate therapy regimens with one or more antiepileptic drugs. Epilepsy surgery has been the standard therapy to help those patients who suffer from drug-resistant epilepsy. The goal of this surgery is to halt or reduce the intensity of seizures. This literature review aims to provide an overview of existing surgical procedures for the treatment of drug-resistant epilepsy and the degree of seizure control they provide based on available literature. Methods: Data were collected from medical journal databases, aggregators, and individual publications. The most used databases were PubMed, Medline and NCBI. Some of the keywords used to search these databases include: “drug resistant epilepsy”, “seizure control”, and “neurosurgery”. Results: Epileptic surgery is divided into resective and non-resective procedures. Studies have shown that a full resection of the epileptogenic brain area increases the probability of seizure eradication, however, the risks of postoperative impairments grow as the resection area is extended. On the other hand, patients who are unsuitable for seizure focus removal by resective surgery, such as those with multifocal seizures or overlapping epileptogenic zone with a functional cortex, may benefit from non-resective surgical options such as Vagus Nerve Stimulation and Responsive Neurostimulation. Conclusion: This literature review discusses the comprehensive treatment of epilepsy, especially the surgical treatment of drug-resistant epilepsy. The reviewed studies have shown that epilepsy surgery has promising outcomes in achieving seizure freedom/reducing seizure frequency with minimal adverse effects when performed correctly with the appropriate choice of surgical candidates.

Transcutaneous Auricular Vagus Nerve Stimulation: From Concept to Application

Whether in the West or the East,the connection between the ear and the rest of the body has been explored for a long time.Especially in the past century or more,the relevant theoretical and applied research on the ear has greatly promoted the development of ear therapy,and finally the concept of transcutaneous auricular vagus nerve stimulation(taVNS)has been proposed.The purpose of taVNS is to treat a disease non-invasively by applying electrical current to the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear.In the past two decades,taVNS has been a topic of basic,clinical,and transformation research.It has been applied as an alternative to drug treatment for a variety of diseases.Based on the rapid understanding of the application of taVNS to human health and disease,some limitations in the development of this field have also been gradually exposed.Here,we comprehensively review the origin and research status of the field.