OBJECTIVE: To explore the brain effect mechanism and the correlation between brain functional imaging and cognitive function in treatment of depressive disorder (DD) with transcutaneous auricular vagus nerve stimulation (taVNS) based on the resting-state functional magenetic reasonance imaging (rs-fMRI). METHODS: Thirty-two DD patients were included in a depression group and 32 subjects of healthy condition were enrolled in a normal group. In the depression group, the taVNS was applied to bilateral Xin (CO₁₅) and Shen (CO₁₀), at disperse-dense wave, 4 Hz/20 Hz in frequency and current intensity ≤20 mA depending on patient's tolerance, 30 min each time, twice daily. The duration of treatment consisted of 8 weeks. The patients of two groups were undertaken rs-fMRI scanning. The scores of Hamilton depression scale (HAMD), Hamilton anxiety scale (HAMA) and Wisconsin card sorting test (WCST) were observed in the normal group at baseline and the depression group before and after treatment separately. The differential brain regions were observed before and after treatment in the two groups and the value of degree centrality (DC) of fMRI was obtained. Their correlation was analyzed in terms of HAMD, HAMA and WCST scores. RESULTS: The scores of HAMD and HAMA in the depression group were all higher than those in the normal group (P<0.05). After treatment, the scores of HAMD and HAMA were lower than those before treatment in the depression group; the scores of total responses, response errors and perseverative errors of WCST were all lower than those before treatment (P<0.05). The brain regions with significant differences included the left inferior temporal gyrus, the left cerebellar peduncles region 1, the left insula, the right putamen, the bilateral supplementary motor area and the right middle frontal gyrus. After treatment, the value of DC in left supplementary motor area was negatively correlated to HAMD and HAMA scores respectively (r=-0.324, P=0.012; r=-0.310, P=0.015); the value of DC in left cerebellar peduncles region 1 was negatively correlated to the total responses of WCST (r=-0.322, P=0.013), and the left insula was positively correlated to the total responses of WCST (r=0.271, P=0.036). CONCLUSION The taVNS can modulate the intensity of the functional activities of some brain regions so as to relieve depressive symptoms and improve cognitive function.
Humans ; Depression/therapy* ; Magnetic Resonance Imaging/methods* ; Vagus Nerve Stimulation/methods* ; Brain/diagnostic imaging* ; Transcutaneous Electric Nerve Stimulation/methods* ; Vagus Nerve

OBJECTIVE: To observe the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the sleep quality and nocturnal heart rate variability (HRV) in patients with primary insomnia. METHODS: Twenty-one patients with primary insomnia were included. Using SDZ-ⅡB electric acupuncture apparatus, Xin (CO₁₅) and Shen (CO₁₀) were stimulated with disperse-dense wave, 4 Hz/ 20 Hz in frequency, (0.2±30%) ms of pulse width and tolerable intensity. Electric stimulation was given once every morning and evening of a day, 30 min each time, for 4 weeks totally. Before and after treatment, the score of Pittsburgh sleep quality index (PSQI), objective sleep structure (total sleep time [TST], sleep latency [SL], wake after sleep onset [WASO], sleep efficiency [SE], the percentages of non-rapid eye movement period 1, 2, 3, and the percentage of rapid eye movement period to TST [N1%, N2%, N3%, REM%] ) and nocturnal HRV (high frequency [HF], low frequency [LF], the ratio of LF to HF [LF/HF], standard deviation for the normal RR intervals [SDNN], squared root of the mean sum of squares of differences between adjacent intervals RR [RMSSD], the percentage of adjacent RR intervals with differences larger than 50 ms in the entire recording [PNN50%], the mean of sinus RR intervals [NNMean] ) were compared in the patients separately. RESULTS: After treatment, the score of each item and the total score of PSQI and SL were all reduced as compared with those before treatment (P<0.01, P<0.001); SE, N3%, LF, HF, LF/HF, SDNN, NNMean and RMSSD were all increased compared with those before treatment (P<0.001, P<0.01). CONCLUSION The taVNS improves the sleep quality and objective sleep structure in patients with primary insomnia, which is probably related to the regulation of autonomic nervous functions.
Heart Rate/physiology* ; Humans ; Sleep/physiology* ; Sleep Initiation and Maintenance Disorders/therapy* ; Vagus Nerve ; Vagus Nerve Stimulation

OBJECTIVE: To explore the modulation of transcutaneous auricular vagus nerve stimulation (taVNS) on default mode network (DMN) in patients with primary insomnia (PI). METHODS: A total of 22 PI patients (one patient dropped off and two patients were excluded) were included and treated with taVNS. The bilateral auricular points of Xin (CO₁₅) and Shen (CO₁₀) were selected and treated with disperse-dense wave at frequency of 4 Hz/20 Hz, the intensity was based on the patient's tolerance. taVNS was given once in the morning and once in the evening for 30 minutes each time. The treatment lasted for at least 5 days a week for 4 weeks. At the same time, 16 healthy subjects matched with gender and age were recruited. The Pittsburgh sleep quality index (PSQI) score was evaluated before and after treatment in PI patients. The resting-state functional magnetic resonance imaging (rs-fMRI) data of PI patients before and after treatment and healthy subjects at baseline period were collected to observe the effect of taVNS on the functional connection (FC) between posterior cingulate cortex (PCC) and whole brain. RESULTS: After treatment, the total score of PSQI in PI patients was lower than that before treatment (P<0.01). Compared with healthy subjects, the FC of the left PCC was increased either with the left orbital superior frontal gyrus or with left middle frontal gyrus (P<0.001), and the FC between right PCC and left middle frontal gyrus was increased in PI patients before treatment (P<0.001). Compared before treatment, the FC between left PCC and left middle frontal gyrus was decreased (P<0.05), and the FC of the right PCC was decreased either with the right medial prefrontal cortex or with the left middle frontal gyrus in PI patients after treatment (P<0.001, P<0.01). CONCLUSION taVNS can modulate the FC between anterior and posterior DMN, and between DMN and cognitive control network of PI patients, which may be one of the brain effect mechanisms of taVNS in the treatment of PI patients.
Brain/physiology* ; Default Mode Network ; Humans ; Magnetic Resonance Imaging/methods* ; Sleep Initiation and Maintenance Disorders/therapy* ; Vagus Nerve ; Vagus Nerve Stimulation/methods*

As non-pharmaceutical interventions, non-invasive electrical neuromodulation techniques are promising in pain management. With many advantages, such as low costs, high usability, and non-invasiveness, they have been exploited to treat multiple types of clinical pain. Proper use of these techniques requires a comprehensive understanding of how they work. In this article, we reviewed recent studies concerning non-invasive electrical peripheral nerve stimulation (transcutaneous electrical nerve stimulation and transcutaneous vagus/vagal nerve stimulation) as well as electrical central nerve stimulation (transcranial direct current stimulation and transcranial alternating current stimulation). Specifically, we discussed their analgesic effects on acute and chronic pain, and the neural mechanisms thereof. We then contrasted the four kinds of nerve stimulation techniques, pointing out limitations of existing studies and proposing directions for future research. With more extensive and in-depth research to overcome these limitations, we shall witness more clinical applications of non-invasive electrical nerve stimulations to alleviate patients' pain and ease the crippling medical and economic burden imposed on patients, their families, and the entire society.
Analgesics ; Chronic Pain ; Humans ; Transcranial Direct Current Stimulation ; Transcutaneous Electric Nerve Stimulation ; Vagus Nerve Stimulation

OBJECTIVES: Vagus nerve stimulation (VNS) is a neuromodulative therapeutic technique for patients with drug-resistant epilepsy who are not suitable for resection or who have experienced a failed resection. This study aims to explore the efficacy and safety of VNS in patients with refractory epilepsy, and to analyze the influential factors for the efficacy. METHODS: A retrospective review of clinical data were conducted for 35 patients, who were treated for refractory epilepsy through VNS surgery in the Department of Neurosurgery, Xiangya Hospital, Central South University from April 2016 to August 2019. All patients were analyzed in terms of the clinical and follow-up data. RESULTS: After a mean follow-up of 26 months (6-47 months), outcome was as follows: 7 patients were MuHugh class I, 13 patients were MuHugh class II, 8 patients were MuHugh class III, and 7 patients were MuHugh class IV-V. The total efficacy rate in the short duration group was significantly higher than that in the long duration group (77.8% vs 50.0%, CONCLUSIONS VNS is a safe and effective option in treating patients with refractory epilepsy, especially for those with short duration.
Drug Resistant Epilepsy/therapy* ; Humans ; Magnetic Resonance Imaging ; Retrospective Studies ; Seizures ; Treatment Outcome ; Vagus Nerve Stimulation

Electroencephalogram (EEG) has been an important tool for scientists to study epilepsy and evaluate the treatment of epilepsy for half a century, since epilepsy seizures are caused by the diffusion of excessive discharge of brain neurons. This paper reviews the clinical application of scalp EEG in the treatment of intractable epilepsy with vagus nerve stimulation (VNS) in the past 30 years. It mainly introduces the prediction of the therapeutic effect of VNS on intractable epilepsy based on EEG characteristics and the effect of VNS on EEG of patients with intractable epilepsy, and expounds some therapeutic mechanisms of VNS. For predicting the efficacy of VNS based on EEG characteristics, EEG characteristics such as epileptiform discharge, polarity of slow cortical potential changes, changes of EEG symmetry level and changes of EEG power spectrum are described. In view of the influence of VNS treatment on patients' EEG characteristics, the change of epileptiform discharge, power spectrum, synchrony, brain network and amplitude of event-related potential P300 are described. Although no representative EEG markers have been identified for clinical promotion, this review paves the way for prospective studies of larger patient populations in the future to better apply EEG to the clinical treatment of VNS, and provides ideas for predicting VNS efficacy, assessing VNS efficacy, and understanding VNS treatment mechanisms, with broad medical and scientific implications.
Drug Resistant Epilepsy ; Electroencephalography ; Humans ; Prospective Studies ; Scalp ; Treatment Outcome ; Vagus Nerve Stimulation

The cholinergic anti-inflammatory pathway (CAP) is a neuro-immunomodulatory pathway,in which acetylcholine (ACh) released by the interaction of vagal nerves with α7 nicotinic acetylcholine receptor (α7nAChR),which prevents the synthesis and release of pro-inflammatory cytokines and ultimately regulates the local or systemic inflammatory response in a feedback manner. It has been shown that there are many possible effective treatments for sepsis, including vagus nerve stimulation by physical therapy, drugs such as acetylcholine receptor agonist and ultrasound therapy.
Acetylcholine ; Humans ; Inflammation ; Neuroimmunomodulation ; Sepsis ; Vagus Nerve Stimulation ; alpha7 Nicotinic Acetylcholine Receptor

The autonomic nervous system plays critical roles in maintaining homeostasis in humans, directly regulating inflammation by altering the activity of the immune system. The cholinergic anti-inflammatory pathway is a well-studied neuroimmune interaction involving the vagus nerve. CD4-positive T cells expressing β2 adrenergic receptors and macrophages expressing the alpha 7 subunit of the nicotinic acetylcholine receptor in the spleen receive neurotransmitters such as norepinephrine and acetylcholine and are key mediators of the cholinergic anti-inflammatory pathway. Recent studies have demonstrated that vagus nerve stimulation, ultrasound, and restraint stress elicit protective effects against renal ischemia-reperfusion injury. These protective effects are induced primarily via activation of the cholinergic anti-inflammatory pathway. In addition to these immunological roles, nervous systems are directly related to homeostasis of renal physiology. Whole-kidney three-dimensional visualization using the tissue clearing technique CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) has illustrated that renal sympathetic nerves are primarily distributed around arteries in the kidneys and denervated after ischemia-reperfusion injury. In contrast, artificial renal sympathetic denervation has a protective effect against kidney disease progression in murine models. Further studies are needed to elucidate how neural networks are involved in progression of kidney disease.
Acetylcholine ; Arteries ; Autonomic Nervous System ; Cholinergic Neurons ; Homeostasis ; Humans ; Immune System ; Inflammation ; Kidney Diseases ; Kidney ; Macrophages ; Nervous System ; Neurotransmitter Agents ; Norepinephrine ; Optogenetics ; Physiology ; Receptors, Adrenergic ; Receptors, Nicotinic ; Reperfusion Injury ; Spleen ; Sympathectomy ; Sympathetic Nervous System ; T-Lymphocytes ; Ultrasonography ; Vagus Nerve ; Vagus Nerve Stimulation

Epilepsy has been known to humankind since antiquity. The surgical treatment of epilepsy began in the early days of neurosurgery and has developed greatly. Many surgical procedures have stood the test of time. However, clinicians treating epilepsy patients are now witnessing a huge tide of change. In 2017, the classification system for seizure and epilepsy types was revised nearly 36 years after the previous scheme was released. The actual difference between these systems may not be large, but there have been many conceptual changes, and clinicians must bid farewell to old terminology. Paradigms in drug discovery are changing, and novel antiseizure drugs have been introduced for clinical use. In particular, drugs that target genetic changes harbor greater therapeutic potential than previous screening-based compounds. The concept of focal epilepsy has been challenged, and now epilepsy is regarded as a network disorder. With this novel concept, stereotactic electroencephalography (SEEG) is becoming increasingly popular for the evaluation of dysfunctioning neuronal networks. Minimally invasive ablative therapies using SEEG electrodes and neuromodulatory therapies such as deep brain stimulation and vagus nerve stimulation are widely applied to remedy dysfunctional epilepsy networks. The use of responsive neurostimulation is currently off-label in children with intractable epilepsy.
Child ; Classification ; Deep Brain Stimulation ; Drug Discovery ; Drug Resistant Epilepsy ; Electrodes ; Electroencephalography ; Epilepsies, Partial ; Epilepsy ; Humans ; Neurons ; Neurosurgery ; Seizures ; Vagus Nerve Stimulation

Epilepsy is one of the major chronic neurological diseases affecting many patients. Resection surgery is the most effective therapy for medically intractable epilepsy, but it is not feasible in all patients. Vagus nerve stimulation (VNS) is an adjunctive neuromodulation therapy that was approved in 1997 for the alleviation of seizures; however, efforts to control epilepsy by stimulating the vagus nerve have been studied for over 100 years. Although its exact mechanism is still under investigation, VNS is thought to affect various brain areas. Hence, VNS has a wide indication for various intractable epileptic syndromes and epilepsy-related comorbidities. Moreover, recent studies have shown anti-inflammatory effects of VNS, and the indication is expanding beyond epilepsy to rheumatoid arthritis, chronic headaches, and depression. VNS yields a more than 50% reduction in seizures in approximately 60% of recipients, with an increase in reduction rates as the follow-up duration increases. The complication rate of VNS is 3–6%, and infection is the most important complication to consider. However, revision surgery was reported to be feasible and safe with appropriate measures. Recently, noninvasive VNS (nVNS) has been introduced, which can be performed transcutaneously without implantation surgery. Although more clinical trials are being conducted, nVNS can reduce the risk of infection and subsequent device failure. In conclusion, VNS has been demonstrated to be beneficial and effective in the treatment of epilepsy and various diseases, and more development is expected in the future.
Arthritis, Rheumatoid ; Brain ; Comorbidity ; Depression ; Drug Resistant Epilepsy ; Epilepsy ; Equipment Failure ; Follow-Up Studies ; Headache Disorders ; Humans ; Seizures ; Transcutaneous Electric Nerve Stimulation ; Vagus Nerve Stimulation ; Vagus Nerve