[Clinical efficacy of auricular vagus nerve stimulation in the treatment of chronic and acute pain : A systematic review]. / Klinische Wirksamkeit der aurikulären Vagusnervstimulation in der Behandlung chronischer und akuter Schmerzen : Eine systematische Übersichtsarbeit.

BACKGROUND: Current guidelines recommend a personalized, multimodal, and interdisciplinary approach for the treatment of chronic pain. Already in the acute treatment of postoperative pain, it can be useful to minimize risk factors for chronification. Auricular vagus nerve stimulation (aVNS) could be an effective non-drug therapy for the treatment of chronic and acute pain. AIM OF THE WORK: The aim of this systematic review is to evaluate the clinical efficacy of aVNS in chronic and acute pain as well as its effect on medication intake. MATERIALS AND METHODS: A systematic literature search was carried out on the application of auricular electrical stimulation in chronic and acute pain. Studies were classified according to their level of evidence and evaluated via the Jadad scale as well as their scientific validity, and then analyzed in terms of indication, method, stimulation parameters, duration of treatment, efficacy, and safety. RESULTS: Twenty studies on chronic pain indications, ten studies on acute postoperative pain, as well as seven studies on experimental acute pain were identified and analyzed. The search revealed a total of n = 1105 aVNS-treated patients. The best evidence on the efficacy of aVNS is available for the indications chronic low back pain, chronic cervical syndrome, chronic abdominal pain, and chronic migraine as well as acute postoperative pain in oocyte aspiration, laparoscopic nephrectomy, and open colorectal surgery. Additionally a significant reduction in analgesic or opiate intake was evident in most studies. In three randomized controlled trials in chronic pain patients, a sustainable pain reduction over a period of up to 12 months was shown. Overall, aVNS was very well tolerated. CONCLUSION: This review indicates that aVNS can be a complementary and effective non-drug treatment for patients with chronic and acute postoperative pain. Future studies in these indications should focus on standardizing and optimizing treatment parameters, inclusion of quality-of-life outcome parameters, and longer follow-up periods to better understand the sustainable therapeutic effect of aVNS.

Modulation of Muscle Tone and Sympathovagal Balance in Cervical Dystonia Using Percutaneous Stimulation of the Auricular Vagus Nerve.

Primary cervical dystonia is characterized by abnormal, involuntary, and sustained contractions of cervical muscles. Current ways of treatment focus on alleviating symptomatic muscle activity. Besides pharmacological treatment, in severe cases patients may receive neuromodulative intervention such as deep brain stimulation. However, these (highly invasive) methods have some major drawbacks. For the first time, percutaneous auricular vagus nerve stimulation (pVNS) was applied in a single case of primary cervical dystonia. Auricular vagus nerve stimulation was already shown to modulate the (autonomous) sympathovagal balance of the body and proved to be an effective treatment in acute and chronic pain, epilepsy, as well as major depression. pVNS effects on cervical dystonia may be hypothesized to rely upon: (i) the alteration of sensory input to the brain, which affects structures involved in the genesis of motoric and nonmotoric dystonic symptoms; and (ii) the alteration of the sympathovagal balance with a sustained impact on involuntary movement control, pain, quality of sleep, and general well-being. The presented data provide experimental evidence that pVNS may be a new alternative and minimally invasive treatment in primary cervical dystonia. One female patient (age 50 years) suffering from therapy refractory cervical dystonia was treated with pVNS over 20 months. Significant improvement in muscle pain, dystonic symptoms, and autonomic regulation as well as a subjective improvement in motility, sleep, and mood were achieved. A subjective improvement in pain recorded by visual analog scale ratings (0-10) was observed from 5.42 to 3.92 (medians). Muscle tone of the mainly affected left and right trapezius muscle in supine position was favorably reduced by about 96%. Significant reduction of muscle tone was also achieved in sitting and standing positions of the patient. Habituation to stimulation leading to reduced stimulation efficiency was observed and counteracted by varying stimulation patterns. Experimental evidence is provided for significantly varied sympathovagal modulation in response to pVNS during sleep, assessed via heart rate variability (HRV). Time domain measures like the root mean square of successive normal to normal heart beat intervals, representing parasympathetic (vagal) activity, increased from 37.8 to 67.6 ms (medians). Spectral domain measures of HRV also show a shift to a more pronounced parasympathetic activity.

Integrated Platform for the Management of Chronic Low Back Pain.

BACKGROUND: Chronic low back pain is a global health problem having a tremendous effect on the quality of life of patients. OBJECTIVES: An online therapy management system (TMS) is developed for comprehensive management of chronic low back pain patients. METHODS: A smartphone and a web app are built based on the Keep-In-Touch Telehealth Platform. The smartphone app allows entering patient reported outcomes and connection to third party devices to monitor physiological data and parameters of therapy. RESULTS: The TMS has been realized and a wearable auricular vagus nerve stimulation device has been integrated. The TMS is currently evaluated in a randomized clinical trial.

Bursted auricular vagus nerve stimulation alters heart rate variability in healthy subjects.

Objective.Recent research suggests that percutaneous auricular vagus nerve stimulation (pVNS) beneficially modulates the autonomic nervous system (ANS). Bursted pVNS seems to be efficient for nerve excitation. Bursted pVNS effects on cardiac autonomic modulation are not disclosed yet.Approach.For the first time, the present study evaluates the effect of pVNS on cardiac autonomic modulation in healthy subjects (n = 9) using two distinct bursted stimulation patterns (biphasic and triphasic stimulation) and heart rate variability analysis (HRV). Stimulation was delivered via four needle electrodes in vagally innervated regions of the right auricle. Each of the two bursted stimulation patterns was applied twice in randomized order over four consecutive stimulation sessions per subject.Main results.Bursted pVNS did not change heart rate, blood pressure, and inflammatory parameters in study subjects. pVNS significantly increased the standard deviation of heart inter-beat intervals, from 46.39 ± 10.4 ms to 63.46 ± 22.47 ms (p < 0.05), and the total power of HRV, from 1475.7 ± 616.13 ms2to 3190.5 ± 2037.0 ms2(p < 0.05). The high frequency (HF) power, the low frequency (LF) power, and theLF/HFratio did not change during bursted pVNS. Both stimulation patterns did not show any significant differences in cardiac autonomic modulation. Stimulation intensity to reach a tingling sensation was significantly lower in triphasic compared to biphasic stimulation (p< 0.05). Bursted stimulation was well tolerated.Significance.Bursted pVNS seems to affect cardiac autonomic modulation in healthy subjects, with no difference between biphasic and triphasic stimulation, the latter requiring lower stimulation intensities. These findings foster implementation of more efficient pVNS stimulation.

Sensitivity Study of Neuronal Excitation and Cathodal Blocking Thresholds of Myelinated Axons for Percutaneous Auricular Vagus Nerve Stimulation.

OBJECTIVE: Excitation of myelinated nerve fibers is investigated by means of numerical simulations, for the application of percutaneous auricular vagus nerve stimulation (pVNS). High sensitivity to axon diameter is of interest regarding the goal of targeting thicker fibers. METHODS: Excitation and blocking thresholds for different pulse types, phase durations, axon depths, axon-electrode distances, temperatures and axon diameters are investigated. The used model consists of a 50 mm long axon and a centrally located needle electrode in a layered medium representing the auricle. Neuronal excitation is simulated using the Frankenhaeuser-Huxley equations for all combinations of parameter values. RESULTS AND CONCLUSION: Multiple modes and locations of excitation along the axon were observed, depending on the pulse type and amplitude. When increasing the axon-electrode distance from 1 mm to 2 mm, sensitivity of thresholds to axon depth decreased with ca. 50%, while sensitivity to axon-electrode distance, axon diameter and phase duration each increased with ca. 15% to 20%, except from monophasic anodal pulses, showing a 45% decrease for axon-electrode distance. These trends for axon diameter and axon-electrode distance allow for more selective stimulation of thicker target fibers using monophasic anodal pulses at higher axon-electrode distances. Cathodal monophasic pulses did not perform well due to blocking of the thicker fibers, which was only rarely seen for other pulse types. SIGNIFICANCE: Sensitivities of stimulation thresholds to these parameters by numerical simulation reveal how the stimulation parameters can be changed in order to increase therapeutic effect and comfort during pVNS by enabling more selective stimulation.

High-Resolution Episcopic Imaging for Visualization of Dermal Arteries and Nerves of the Auricular Cymba Conchae in Humans.

Therapeutic applications of auricular vagus nerve stimulation (VNS) have drawn recent attention. Since the targeted stimulation process and parameters depend on the electrode-tissue interaction, the lack of structural anatomical information on innervation and vascularization of the auricle restrain the current optimization of stimulation paradigms. For the first time, we employed high-resolution episcopic imaging (HREM) to generate histologic volume data from donated human cadaver ears. Optimal parameters for specimen preparation were evaluated. Anatomical 3D vascular and nerve structures were reconstructed in one sample of an auricular cymba conchae (CC). The feasibility of HREM to visualize anatomical structures was assessed in that diameters, occupied areas, volumes, and mutual distances between auricular arteries, nerves, and veins were registered. The selected region of CC (3 × 5.5 mm) showed in its cross-sections 21.7 ± 2.7 (mean ± standard deviation) arteries and 14.66 ± 2.74 nerve fibers. Identified nerve diameters were 33.66 ± 21.71 µm, and arteries had diameters in the range of 71.58 ± 80.70 µm. The respective occupied area showed a share of, on average, 2.71% and 0.3% for arteries and nerves, respectively, and similar volume occupancy for arteries and nerves. Inter-centroid minimum distance between arteries and nerves was 274 ± 222 µm. The density of vessels and nerves around a point within CC on a given grid was assessed, showing that 50% of all vessels and nerves were found in a radial distance of 1.6-1.8 mm from any of these points, which is strategically relevant when using stimulation needles in the auricle for excitation of nerves. HREM seems suitable for anatomical studies of the human ear. A 3D model of CC was established in the micrometer scale, which forms the basis for future optimization of the auricular VNS. Obviously, the presented single cadaver study needs to be validated by additional anatomical data on the innervation and vascularization of the auricle.

Stimulation Pattern Efficiency in Percutaneous Auricular Vagus Nerve Stimulation: Experimental Versus Numerical Data.

OBJECTIVE: Percutaneous electrical stimulation of the auricular vagus nerve (pVNS) is an electroceutical technology. The selection of stimulation patterns is empirical, which may lead to under-stimulation or over-stimulation. The objective is to assess the efficiency of different stimulation patterns with respect to individual perception and to compare it with numerical data based on in-silico ear models. METHODS: Monophasic (MS), biphasic (BS) and triphasic stimulation (TS) patterns were tested in volunteers. Different clinically-relevant perception levels were assessed. In-silico models of the human ear were created with embedded fibers and vessels to assess different excitation levels. RESULTS: TS indicates experimental superiority over BS which is superior to MS while reaching different perception levels. TS requires about 57% and 35% of BS and MS magnitude, respectively, to reach the comfortable perception. Experimental thresholds decrease from non-bursted to bursted stimulation. Numerical results indicate a slight superiority of BS and TS over MS while reaching different excitation levels, whereas the burst length has no influence. TS yields the highest number of asynchronous action impulses per stimulation symbol for the used tripolar electrode set-up. CONCLUSION: The comparison of experimental and numerical data favors the novel TS pattern. The analysis separates excitatory pVNS effects in the auricular periphery, as accounted by in-silico data, from the combination of peripheral and central pVNS effects in the brain, as accounted by experimental data. SIGNIFICANCE: The proposed approach moves from an empirical selection of stimulation patterns towards efficient and optimized pVNS settings.

Non-invasive Auricular Vagus Nerve Stimulation as a Potential Treatment for Covid19-Originated Acute Respiratory Distress Syndrome.

Background: Covid-19 is an infectious disease caused by an invasion of the alveolar epithelial cells by coronavirus 19. The most severe outcome of the disease is the Acute Respiratory Distress Syndrome (ARDS) combined with hypoxemia and cardiovascular damage. ARDS and co-morbidities are associated with inflammatory cytokine storms, sympathetic hyperactivity, and respiratory dysfunction. Hypothesis: In the present paper, we present and justify a novel potential treatment for Covid19-originated ARDS and associated co-morbidities, based on the non-invasive stimulation of the auricular branch of the vagus nerve. Methods: Auricular vagus nerve stimulation activates the parasympathetic system including anti-inflammatory pathways (the cholinergic anti-inflammatory pathway and the hypothalamic pituitary adrenal axis) while regulating the abnormal sympatho-vagal balance and improving respiratory control. Results: Along the paper (1) we expose the role of the parasympathetic system and the vagus nerve in the control of inflammatory processes (2) we formulate our physiological and methodological hypotheses (3) we provide a large body of clinical and preclinical data that support the favorable effects of auricular vagus nerve stimulation in inflammation, sympatho-vagal balance as well as in respiratory and cardiac ailments, and (4) we list the (few) possible collateral effects of the treatment. Finally, we discuss auricular vagus nerve stimulation protective potential, especially in the elderly and co-morbid population with already reduced parasympathetic response. Conclusions: Auricular vagus nerve stimulation is a safe clinical procedure and it could be either an effective treatment for ARDS originated by Covid-19 and similar viruses or a supplementary treatment to actual ARDS therapeutic approaches.

Current Directions in the Auricular Vagus Nerve Stimulation I - A Physiological Perspective.

Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging technology in the field of bioelectronic medicine with applications in therapy. Modulation of the afferent vagus nerve affects a large number of physiological processes and bodily states associated with information transfer between the brain and body. These include disease mitigating effects and sustainable therapeutic applications ranging from chronic pain diseases, neurodegenerative and metabolic ailments to inflammatory and cardiovascular diseases. Given the current evidence from experimental research in animal and clinical studies we discuss basic aVNS mechanisms and their potential clinical effects. Collectively, we provide a focused review on the physiological role of the vagus nerve and formulate a biology-driven rationale for aVNS. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the framework of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on physiological aspects - a discussion of engineering aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.

Current Directions in the Auricular Vagus Nerve Stimulation II - An Engineering Perspective.

Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging electroceutical technology in the field of bioelectronic medicine with applications in therapy. Artificial modulation of the afferent vagus nerve - a powerful entrance to the brain - affects a large number of physiological processes implicating interactions between the brain and body. Engineering aspects of aVNS determine its efficiency in application. The relevant safety and regulatory issues need to be appropriately addressed. In particular, in silico modeling acts as a tool for aVNS optimization. The evolution of personalized electroceuticals using novel architectures of the closed-loop aVNS paradigms with biofeedback can be expected to optimally meet therapy needs. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the scope of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on engineering aspects - a discussion of physiological aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.

Higuchi Fractal Dimension of Heart Rate Variability During Percutaneous Auricular Vagus Nerve Stimulation in Healthy and Diabetic Subjects.

Analysis of heart rate variability (HRV) can be applied to assess the autonomic nervous system (ANS) sympathetic and parasympathetic activity. Since living systems are non-linear, evaluation of ANS activity is difficult by means of linear methods. We propose to apply the Higuchi fractal dimension (HFD) method for assessment of ANS activity. HFD measures complexity of the HRV signal. We analyzed 45 RR time series of 84 min duration each from nine healthy and five diabetic subjects with clinically confirmed long-term diabetes mellitus type II and with diabetic foot ulcer lasting more than 6 weeks. Based on HRV time series complexity analysis we have shown that HFD: (1) discriminates healthy subjects from patients with diabetes mellitus type II; (2) assesses the impact of percutaneous auricular vagus nerve stimulation (pVNS) on ANS activity in normal and diabetic conditions. Thus, HFD may be used during pVNS treatment, to provide stimulation feedback for on-line regulation of therapy in a fast and robust way.

Numerical modeling of percutaneous auricular vagus nerve stimulation: a realistic 3D model to evaluate sensitivity of neural activation to electrode position.

OBJECTIVE: Percutaneous stimulation of the auricular branch of the vagus nerve (pVNS) by miniaturized needle electrodes in the auricle gained importance as a treatment for acute and chronic pain. The objective is to establish a realistic numerical model of pVNS and investigate the effects of stimulation waveform, electrodes' depth, and electrodes' position on nerve excitation threshold and the percentage of stimulated nerves. METHODS: Simulations were performed with Sim4Life. An electrostatic solver and neural tissue models were combined for electromagnetic and neural simulation. The numerical model consisted of a realistic high-resolution model of a human ear, blood vessels, nerves, and three needle electrodes. RESULTS: A novel 3D ear model was established, including blood vessels and nerves. The electric field distribution was extracted and evaluated. Maximum sensitivity to needles' depth and displacement was evaluated to be 9.8 and 15.5% per 0.1 mm, respectively. Stimulation was most effective using biphasic compared to mono-phasic pulses. CONCLUSION: The established model allows easy and quantitative evaluation of various stimulation setups, enabling optimization of pVNS in experimental settings. Results suggest a high sensitivity of pVNS to the electrodes' position and depth, implying the need for precise electrode positioning. Validation of the model needs to be performed.

Effects of individualized electrical impedance tomography and image reconstruction settings upon the assessment of regional ventilation distribution: Comparison to 4-dimensional computed tomography in a porcine model.

Electrical impedance tomography (EIT) is a promising imaging technique for bedside monitoring of lung function. It is easily applicable, cheap and requires no ionizing radiation, but clinical interpretation of EIT-images is still not standardized. One of the reasons for this is the ill-posed nature of EIT, allowing a range of possible images to be produced-rather than a single explicit solution. Thus, to further advance the EIT technology for clinical application, thorough examinations of EIT-image reconstruction settings-i.e., mathematical parameters and addition of a priori (e.g., anatomical) information-is essential. In the present work, regional ventilation distribution profiles derived from different EIT finite-element reconstruction models and settings (for GREIT and Gauss Newton) were compared to regional aeration profiles assessed by the gold-standard of 4-dimensional computed tomography (4DCT) by calculating the root mean squared error (RMSE). Specifically, non-individualized reconstruction models (based on circular and averaged thoracic contours) and individualized reconstruction models (based on true thoracic contours) were compared. Our results suggest that GREIT with noise figure of 0.15 and non-uniform background works best for the assessment of regional ventilation distribution by EIT, as verified versus 4DCT. Furthermore, the RMSE of anteroposterior ventilation profiles decreased from 2.53±0.62% to 1.67±0.49% while correlation increased from 0.77 to 0.89 after embedding anatomical information into the reconstruction models. In conclusion, the present work reveals that anatomically enhanced EIT-image reconstruction is superior to non-individualized reconstruction models, but further investigations in humans, so as to standardize reconstruction settings, is warranted.