Selective Nerve Stimulation Research Articles

Highly efficient modeling and optimization of neural fiber responses to electrical stimulation

Peripheral neuromodulation has emerged as a powerful modality for controlling physiological functions and treating a variety of medical conditions including chronic pain and organ dysfunction. The underlying complexity of the nonlinear responses to electrical stimulation make it challenging to design precise and effective neuromodulation protocols. Computational models have thus become indispensable in advancing our understanding and control of neural responses to electrical stimulation. However, existing approaches suffer from computational bottlenecks, rendering them unsuitable for real-time applications, large-scale parameter sweeps, or sophisticated optimization. In this work, we introduce an approach for massively parallel estimation and optimization of neural fiber responses to electrical stimulation using machine learning techniques. By leveraging advances in high-performance computing and parallel programming, we present a surrogate fiber model that generates spatiotemporal responses to a wide variety of cuff-based electrical peripheral nerve stimulation protocols. We used our surrogate fiber model to design stimulation parameters for selective stimulation of pig and human vagus nerves. Our approach yields a several-orders-of-magnitude improvement in computational efficiency while retaining generality and high predictive accuracy, demonstrating its robustness and potential to enhance the design and optimization of peripheral neuromodulation therapies.

Towards spatially selective efferent neuromodulation: anatomical and functional organization of cardiac fibres in the porcine cervical vagus nerve.

Spatially selective vagus nerve stimulation (sVNS) offers a promising approach for addressing heart disease with enhanced precision. Despite its therapeutic potential, VNS is limited by off-target effects and the need for time-consuming titration. Our research aimed to determine the spatial organization of cardiac afferent and efferent fibres within the vagus nerve of pigs to achieve targeted neuromodulation. Using trial-and-error sVNS in vivo and ex vivo micro-computed tomography fascicle tracing, we found significant spatial separation between cardiac afferent and cardiac efferent fibres at the mid-cervical level and they were localized on average on opposite sides of the nerve cross-section. This was consistent between both in vivo and ex vivo methods. Specifically, cardiac afferent fibres were located near pulmonary fibres, consistent with findings of cardiopulmonary convergent circuits and, notably, cardiac efferent fascicles were exclusive. These cardiac efferent regions were located in close proximity to the recurrent laryngeal regions. This is consistent with the roughly equitable spread across the nerve of the afferent and efferent fibres. Our study demonstrated that targeted neuromodulation via sVNS could achieve scalable heart rate decreases without eliciting cardiac afferent-related reflexes; this is desirable for reducing sympathetic overactivation associated with heart disease. These findings indicate that understanding the spatial organization of cardiac-related fibres within the vagus nerve can lead to more precise and effective VNS therapy, minimizing off-target effects and potentially mitigating the need for titration. KEY POINTS: Spatially selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibres in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects such as scalable heart rate decrease without stimulating cardiac afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and potentially eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions.

Design of an adaptable intrafascicular electrode (AIR) for selective nerve stimulation by model-based optimization.

Peripheral nerve stimulation is being investigated as a therapeutic tool in several clinical scenarios. However, the adopted devices have restricted ability to obtain desired outcomes with tolerable off-target effects. Recent promising solutions are not yet employed in clinical practice due to complex required surgeries, lack of long-term stability, and implant invasiveness. Here, we aimed to design a neural interface to address these issues, specifically dimensioned for pudendal and sacral nerves to potentially target sexual, bladder, or bowel dysfunctions. We designed the adaptable intrafascicular radial electrode (AIR) through realistic computational models. They account for detailed human anatomy, inhomogeneous anisotropic conductance, following the trajectories of axons along curving and branching fascicles, and detailed biophysics of axons. The model was validated against available experimental data. Thanks to computationally efficient geometry-based selectivity estimations we informed the electrode design, optimizing its dimensions to obtain the highest selectivity while maintaining low invasiveness. We then compared the AIR with state-of-the-art electrodes, namely InterStim leads, multipolar cuffs and transversal intrafascicular multichannel electrodes (TIME). AIR, comprising a flexible substrate, surface active sites, and radially inserted intrafascicular needles, is designed to be implanted in a few standard steps, potentially enabling fast implants. It holds potential for repeatable stimulation outcomes thanks to its radial structural symmetry. When compared in-silico, AIR consistently outperformed cuff electrodes and InterStim leads in terms of recruitment threshold and stimulation selectivity. AIR performed similarly or better than a TIME, with quantified less invasiveness. Finally, we showed how AIR can adapt to different nerve sizes and varying shapes while maintaining high selectivity. The AIR electrode shows the potential to fill a clinical need for an effective peripheral nerve interface. Its high predicted performance in all the identified requirements was enabled by a model-based approach, readily applicable for the optimization of electrode parameters in any peripheral nerve stimulation scenario.

Afferent selective vagus nerve stimulation reduces TLR7 induced acute lung inflammation

Background: Vagus nerve stimulation (VNS) has recently been introduced as a nonpharmacological therapy for disease characterized by an exacerbated immune response, with clinical trials demonstrating its efficacy for autoimmunity and sepsis by reducing inflammatory proteins and improving disease scores. To date, much of these anti-inflammatory effects have been attributed to vagal efferent (motor) signaling in a mechanism referred to as the cholinergic anti-inflammatory pathway (CAIP). Recent studies from our lab, as well as others, have begun to highlight alternative neuro-immune regulation by the vagus nerve, independent from the CAIP. The scope of these neuro-immune interactions, including target tissues and cell types, however, is still unclear. Although the lung is densely innervated, it is unknown how VNS can reduce acute TLR7 agonist-induced lung inflammation. Hypothesis: We sought to determine whether VNS was effective at reducing acute lung inflammation induced by viral mimetic and TLR7/8 agonist Resiquimod (R848). Methods: The right cervical vagus nerves of C57BL/6 mice were stimulated electrically (5V, 5Hz) for 20 minutes. A 0.25mg/kg dose of R848 was instilled 10 minutes after beginning VNS. 1 hour post-R848 challenge, relevant tissues were prepared for qPCR, flow cytometry, or ELISA. Results: Stimulation of the right vagus nerve was able to significantly decrease R848-induced mRNA expression of pro-inflammatory cytokines TNFα and IFNβ, as well as chemokines CCL4 and CXCL1 within the lung. This decrease occurred independently of the cells responsible for the CAIP (CD4+ ChAT+ T-cells), indicating a novel neuro-immune mechanism with a new target organ. Flow cytometry revealed that alveolar macrophages and neutrophils were the primary immune cell populations responding to R848 and subsequently modified by VNS, with significant reductions in intracellular staining for TNFα. Epinephrine and norepinephrine were significantly elevated within the serum during the first 5 minutes of VNS, but fluid from bronchoalveolar lavage revealed significant increases of only epinephrine within the lung. Subsequently, removal of the adrenal glands, the primary source of epinephrine, eliminated the anti-inflammatory effect of VNS. Elevation of epinephrine suggests an immunomodulatory role for the β2AR, with further studies using a highly selective antagonist ICI 118 551 or β2AR KO mice eliminating VNS-induced protection. Finally, using optogenetics we were able to identify vagal afferent neurons as the fibers responsible for modulating immune cell activation within the lung. Conclusion: These studies highlight a novel neuro-immune mechanism within the lung capable of regulating viral mimetic-induced inflammation. Facilitated by vagal afferent neurons, we show that VNS elicits adrenal gland-derived epinephrine release that acts through the β2AR to reduce macrophage activation and neutrophil recruitment in the lung. Chan-Zuckerberg Initiative (2020-217656); Graduate Student Support Program (UC Davis: School of Veterinary Medicine); NIH T32 GM (GM099608, GM144303) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A combined cuff electrode array for organ-specific selective stimulation of vagus nerve enabled by Electrical Impedance Tomography.

Previously developed spatially-selective Vagus Nerve Stimulation (sVNS) allows the targeting of specific nerve fascicles through current steering in a multi-electrode nerve cuff but relies on a trial-and-error strategy to identify the relative orientation between electrodes and fascicles. Fast Neural Electrical Impedance Tomography (FN-EIT) has been recently used for imaging neural traffic in the vagus nerves of pigs in a cross-correlation study with sVNS and MicroCT fascicle tracking. FN-EIT has the potential for allowing targeted sVNS; however, up to now, stimulation and imaging have been performed with separate electrode arrays. In this study, different options were evaluated in-silico to integrate EIT and stimulation into a single electrode array without affecting spatial selectivity. The original pig vagus EIT electrode array geometry was compared with a geometry integrating sVNS and EIT electrodes, and with direct use of sVNS electrodes for EIT imaging. Modelling results indicated that both new designs could achieve image quality similar to the original electrode geometry in all tested markers (e.g., co-localisation error <100 µm). The sVNS array was considered to be the simplest due to the lower number of electrodes. Experimental results from testing evoked EIT imaging of recurrent laryngeal activity using electrodes from the sVNS cuff returned a signal-to-noise ratio similar to our previous study (3.9 ± 2.4 vs. 4.1 ± 1.5, N = 4 nerves from 3 pigs) and a lower co-localisation error (≈14% nerve diameter vs. ≈25%, N = 2 nerves from 2 pigs). Performing FN-EIT and sVNS on the same nerve cuff will facilitate translation to humans, simplify surgery and enable targeted neuromodulation strategies.

Getting into shape: the tongue and hypoglossal nerve stimulation.

Subscription RequiredCommentaryGetting into shape: the tongue and hypoglossal nerve stimulation David R. Hillman, MBBS David R. Hillman, MBBS Centre for Sleep Science, School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia Search for more papers by this author Published Online:March 1, 2023https://doi.org/10.5664/jcsm.10550

Changes in tongue morphology predict responses in pharyngeal patency to selective hypoglossal nerve stimulation.

The major goal of the study was to determine whether changes in tongue morphology under selective hypoglossal nerve therapy for obstructive sleep apnea were associated with alterations in airway patency during sleep when specific portions of the hypoglossal nerve were stimulated. This case series was conducted at the Johns Hopkins Sleep Disorders Center at Johns Hopkins Bayview Medical Center. Twelve patients with apnea implanted with a multichannel targeted hypoglossal nerve-stimulating system underwent midsagittal ultrasound tongue imaging during wakefulness. Changes in tongue shape were characterized by measuring the vertical height and polar dimensions between tongue surface and genioglossi origin in the mandible. Changes in patency were characterized by comparing airflow responses between stimulated and adjacent unstimulated breaths during non-rapid eye movement sleep. Two distinct morphologic responses were observed. Anterior tongue base and hyoid-bone movement (5.4 [0.4] to 4.1 [1.0] cm (median and [interquartile range]) with concomitant increases in tongue height (5.0 [0.9] to 5.6 [0.7] cm) were associated with decreases in airflow during stimulation. In contrast, comparable anterior hyoid movement (tongue protrusion from 5.8 [0.5] to 4.5 [0.9] cm) without significant increases in height (5.2 [1.6] to 4.6 [0.8] cm) were associated with marked increases in airflow during sleep. Tongue protrusion with preservation of tongue shape predicted increases in patency, whereas anterior movement with concomitant increases in height were associated with decreased pharyngeal patency. These findings suggest that pharyngeal patency can be best stabilized by stimulating lingual muscles that maintain tongue shape while protruding the tongue, thereby preventing it from prolapsing posteriorly during sleep. Fleury Curado T, Pham L, Otvos T, etal. Changes in tongue morphology predict responses in pharyngeal patency to selective hypoglossal nerve stimulation. J Clin Sleep Med. 2023;19(5):947-955.

Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect

Electrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles—a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses. However, it remains unclear if placement can alter the balance between intended effect and limiting side effect. We used an FDA investigational device exemption approved six-contact epineural cuff to deliver VNS in pigs and quantified how epineural electrode location impacts on- and off-target VNS activation. Detailed post-mortem histology was conducted to understand how the underlying neuroanatomy impacts observed functional responses. Here we report the discovery and characterization of clear neuroanatomy-dependent differences in threshold and saturation for responses related to both effect (change in heart rate) and side effect (neck muscle contractions). The histological and electrophysiological data were used to develop and validate subject-specific computation models of VNS, creating a well-grounded quantitative framework to optimize electrode location-specific activation of nerve fibers governing intended effect versus unwanted side effect.

A Soft and Stretchable Multielectrode Cuff for Selective Peripheral Nerve Stimulation

AbstractBioelectronic medicine can treat diseases and disorders in humans by electrically interfacing with peripheral nerves. Multielectrode cuffs can be used for selective stimulation of portions of the nerve, which is advantageous for treatment specificity. The biocompatibility and conformability of cuffs can be improved by reducing the mechanical mismatch between nerve tissue and cuffs, but selective stimulation of nerves has yet to be achieved with soft and stretchable cuff electrodes. Here, this paper reports the development of a soft and stretchable multielectrode cuff (sMEC) for selective nerve stimulation. The device is made of 50 µm thick silicone with embedded gold nanowire conductors, which renders it functional at 50% strain, and provides superior conformability for wrapping nerves. By using different stimulation protocols, high functional selectivity is achieved with the sMEC's eight stimulation electrodes in a porcine sciatic nerve model. Finite element modeling is used to predict the potential distribution within the nerve, which correlate well with the achieved stimulation results. Recent studies are showing that mechanical softness is of outermost importance for reducing foreign body response. It is therefore believed that the soft high‐performance sMEC technology is ideal for future selective peripheral nerve interfaces for bioelectronic medicine.

Feasibility of transesophageal phrenic nerve stimulation

BackgroundEvery year, more than 2.5 million critically ill patients in the ICU are dependent on mechanical ventilation. The positive pressure in the lungs generated by the ventilator keeps the diaphragm passive, which can lead to a loss of myofibers within a short time. To prevent ventilator-induced diaphragmatic dysfunction (VIDD), phrenic nerve stimulation may be used.ObjectiveThe goal of this study is to show the feasibility of transesophageal phrenic nerve stimulation (TEPNS). We hypothesize that selective phrenic nerve stimulation can efficiently activate the diaphragm with reduced co-stimulations.MethodsAn in vitro study in saline solution combined with anatomical findings was performed to investigate relevant stimulation parameters such as inter-electrode spacing, range to target site, or omnidirectional vs. sectioned electrodes. Subsequently, dedicated esophageal electrodes were inserted into a pig and single stimulation pulses were delivered simultaneously with mechanical ventilation. Various stimulation sites and response parameters such as transdiaphragmatic pressure or airway flow were analyzed to establish an appropriate stimulation setting.ResultsPhrenic nerve stimulation with esophageal electrodes has been demonstrated. With a current amplitude of 40 mA, similar response figures of the diaphragm activation as compared to conventional stimulation with needle electrodes at 10mA were observed. Directed electrodes best aligned with the phrenic nerve resulted in up to 16.9 % higher amplitude at the target site in vitro and up to 6 cmH20 higher transdiaphragmatic pressure in vivo as compared to omnidirectional electrodes. The activation efficiency was more sensitive to the stimulation level inside the esophagus than to the inter-electrode spacing. Most effective and selective stimulation was achieved at the level of rib 1 using sectioned electrodes 40 mm apart.ConclusionDirected transesophageal phrenic nerve stimulation with single stimuli enabled diaphragm activation. In the future, this method might keep the diaphragm active during, and even support, artificial ventilation. Meanwhile, dedicated sectioned electrodes could be integrated into gastric feeding tubes.

Changes in Tongue Morphology Predict Responses in Pharyngeal Patency to Selective Hypoglossal Nerve Stimulation

Changes in Tongue Morphology Predict Responses in Pharyngeal Patency to Selective Hypoglossal Nerve Stimulation

Fascicular Organisation and Neuroanatomy of the Porcine and Human Vagus Nerves: Allowing for Spatially Selective Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) often results in off‐target effects due to the unknown fascicular organisation of the cervical vagus nerve and thus nonspecific nature of stimulation. This currently limits its therapeutic efficacy in treating epilepsy and depression and restricts its extension to treating numerous other conditions, such as heart failure and lung injury, for which it could be a promising treatment. The purpose of this work was to determine the fascicular anatomical representation of the recurrent laryngeal, cardiac and pulmonary branches of the vagus nerve at the mid‐cervical level of VNS cuff placement in the vagus nerve in pigs using micro‐computed tomography (microCT) to trace anatomical connections to end‐organs with the intention of extension to humans.The left vagus nerves were dissected from mid‐cervical level to the branches of the lungs, heart and larynx in four domestic female 60‐70 kg pigs. Nerves were fixed, sectioned into 4 cm lengths with registration landmarks, soaked in Lugol’s solution (1% total iodine) for five days for sufficient contrast staining and microCT‐scanned (Nikon XT H 225, Nikon Metrology) with a molybdenum target and 7 µm voxel size, 35 kVp energy, 114 mA current, 4 W power, 0.25 fps in 4 s exposure time, and 3176 projections. Subsequently, scans were reconstructed in CT Pro 3D (Nikon Metrology) and analysed in ImageJ. Fascicles of the three target organs/fascicle groups were segmented and traced with Neurolucida 360 (MBF Bioscience) from the point the organ‐specific branch enters the vagus nerve to mid‐cervical level (20‐25 cm total length per nerve).The three identified fascicular groups remained discrete at the cervical level (26%, 23% and 4% of total vagus nerve area for pulmonary, recurrent laryngeal and cardiac fascicle groups, respectively, with significant separation of centres of mass (P&lt;0.05)). These three distinct regions contained overlap only between a small number of pulmonary and recurrent laryngeal fascicles (&lt;11%). The cardiac fascicles remained separate. This confirms organotopic organisation of the cervical vagus nerve according to organ/function for cardiac, pulmonary and recurrent laryngeal fascicles. Work is in progress to delineate similar fascicular organisation in excised cadaveric human vagus nerves. Knowledge of the fascicular organisation of the vagus nerve will enable accurate spatially selective VNS which may allow for avoidance of off‐target effects and so improve its therapeutic efficacy.

Current role of neuromodulation in bladder pain syndrome/interstitial cystitis.

Neuromodulation is recommended by major international guidelines as a fourth-line treatment in bladder pain syndrome/interstitial cystitis (BPS/IC) patients after failure of behavioural, oral and intravesical pharmacological treatments, including hydrodistension. A non-systematic review of studies identified by electronic search of MEDLINE was performed with no time limitation. A narrative synthesis of the existing evidence regarding the results of sacral, tibial and pudendal nerve stimulation in the management of BPS/IC was developed. Neuromodulation in pelvic chronic pain disorders, including BPS/IC, is a useful tool for refractory patients to conventional treatments. Sacral neuromodulation may be effective in patients with BPS without Hunner's lesions, and the effect seems to be maintained in the mid- and long-term. Posterior tibial nerve stimulation can be offered to patients with BPS/IC in the context of a multidisciplinary approach. When pudendal neuralgia is suspected, selective pudendal nerve stimulation has a high response rate. The aetiology of the pain can influence the outcomes in the mid- and long-term of the different neuromodulation approaches, thus careful diagnosis is recommended.

English MODULATION OF MELATONIN SECRETION WITH TRANSCUTANEOUS AURICULAR NERVE STIMULATION: A CASE STUDY

The main study objective was to test the hypothesis that selective electrical transcutaneous auricular nerve stimulation (tANS) under forenoon daylight conditions induces melatonin secretion in a 64-year-old male patient with angina pectoris, hypercholesterolomy and coronary artery disease, assuming that it has beneficial effects on accompanied insomnia (Regensburg Insomnia Scale (RIS) = 22 points, the total score ranges from 0 to 40). Silicone stimulation plugs, with two platinum stimulating cathodes each, were inserted into the left and right external ears. Afterwards, one-second-long pulse trains of cathodic, biphasic and current regulated stimulating pulses at stimulating charge density Cd of 50.88 µC/cm2 and frequency of 25 Hz, were delivered for 30 min to selected sites at the upper and lower part of the left and right Cymba Conchae (CC), respectively. The common anode was attached to the neck. The time gap between the pulse trains was measured by the patient using a tactile sensor and was about 250 ms. The results showed that selective tANS under forenoon daylight conditions increased melatonin saliva levels in all the trials accomplished in a patient. Precisely, the lowest increase was obtained in trials with lower right (LR) CC, while the highest increase was obtained in upper-right (UR) CC trials.

Ultrasound Shear Wave Elastography of the Tongue during Selective Hypoglossal Nerve Stimulation in Patients with Obstructive Sleep Apnea Syndrome

Currently, there is no established technique to directly measure extrinsic tongue muscle activation during selective hypoglossal stimulation therapy (sHNS) in patients with obstructive sleep apnea syndrome (OSAS) in a simple, non-invasive clinical setting. Ultrasound shear-wave elastography (US-SWE) enables quantitative measurement of tissue stiffness. We investigated whether US-SWE is able to detect changes in muscle stiffness of the tongue during sHNS. Patients with OSAS treated with sHNS were prospectively enrolled. A standardized US-SWE protocol was used to selectively measure tissue stiffness of the geniohyoid muscle (GH) and genioglossus (GG) muscles on the side of stimulator implantation (sGH, sGG) and on the contralateral side (nGH, nGG) without and with sHNS. Eighteen patients were included (median age = 62 years, interquartile range: 56–65, 83.3% male). Median shear-wave velocity (SWV) increased during contraction with each patient's clinically prescribed therapeutic regimen in the sGH (+19%, p = 0.020) and sGG (+81%, p < 0.001) and decreased during contraction in the nGH (–8%, p = 0.107) and nGG (–8%, p = 0.396). Differences in SWV during contraction were significant only on the side of stimulation (sGG +81%, sGH +19%). SWE measurements had excellent reliability as reflected by a Cronbach α value ≥0.9 for all target muscles pre- and post-contraction and an item–total correlation ≥0.5. US-SWE allows reliable measurement of SWV as an indicator of muscle stiffness of extrinsic tongue muscles. This non-invasive method provides new possibilities to distinguish and characterize responders from non-responders in hypoglossal stimulation therapy. Compared with the regular visual assessment of tongue movement, US-SWE of individual muscle groups provides a new non-invasive imaging tool in patients with OSAS.

Selective stimulation of the ferret abdominal vagus nerve with multi-contact nerve cuff electrodes

Dysfunction and diseases of the gastrointestinal (GI) tract are a major driver of medical care. The vagus nerve innervates and controls multiple organs of the GI tract and vagus nerve stimulation (VNS) could provide a means for affecting GI function and treating disease. However, the vagus nerve also innervates many other organs throughout the body, and off-target effects of VNS could cause major side effects such as changes in blood pressure. In this study, we aimed to achieve selective stimulation of populations of vagal afferents using a multi-contact cuff electrode wrapped around the abdominal trunks of the vagus nerve. Four-contact nerve cuff electrodes were implanted around the dorsal (N = 3) or ventral (N = 3) abdominal vagus nerve in six ferrets, and the response to stimulation was measured via a 32-channel microelectrode array (MEA) inserted into the left or right nodose ganglion. Selectivity was characterized by the ability to evoke responses in MEA channels through one bipolar pair of cuff contacts but not through the other bipolar pair. We demonstrated that it was possible to selectively activate subpopulations of vagal neurons using abdominal VNS. Additionally, we quantified the conduction velocity of evoked responses to determine what types of nerve fibers (i.e., Aδ vs. C) responded to stimulation. We also quantified the spatial organization of evoked responses in the nodose MEA to determine if there is somatotopic organization of the neurons in that ganglion. Finally, we demonstrated in a separate set of three ferrets that stimulation of the abdominal vagus via a four-contact cuff could selectively alter gastric myoelectric activity, suggesting that abdominal VNS can potentially be used to control GI function.

In Vivo Evaluation of Fractal Microelectrodes Towards a More Targeted and Energy‐Efficient Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is a moderately effective treatment option for intractable epilepsy, depression, and pain, with promising applications in the treatment of gastrointestinal motility disorders like gastroparesis. The wide-ranging potential indications of VNS suggest an opportunity for a better understanding of underlying neural circuits that can be targeted using microscale electrodes. However, microscale Platinum (Pt) electrodes often have limited charge injection capacity due to their high impedance. Recently, we experimentally demonstrated that microscale Pt electrodes with Vicsek fractal geometry can facilitate electrochemical charge transfer more efficiently with 57% higher cathodic charge storage capacity than conventional circular microelectrodes. Here we are investigating whether the fractal electrode may be more effective in eliciting small fibers in the vagus nerve with less energy consumption due to its enhanced charge injection capability. To evaluate the in vivo performance of these novel microelectrode designs and to determine whether these electrodes are capable of stimulating small, unmyelinated C fibers that supply the stomach, we designed a cuff electrode with an array with four pairs of fractal and circular microelectrode to explore the possibility of radial selective stimulation of vagus nerve. We determined the dimension of the cuff to be 760 μm in diameter to wrap around a rat's vagus nerve so that it can withstand the swelling of the nerve from chronic implantation. We patterned fractal microelectrode to have a geometrical surface area equivalent to that of a circle with 100 μm of diameter. Using a rat model, we have stimulated the right cervical vagus nerve with fractal/circular electrode and recorded the compound action potential (CAP) distal from the stimulation site with 5-7 mm of conduction distance or the dorsal trunk of the abdominal vagus (conduction distance: 70 mm). We used an autonomous neural control (ANC) system, which can stimulate and record from the nerve with randomized stimulus parameter combinations (pulse amplitude: 0-0.4 mA, pulse width: 0.02-1 ms). We adapted a cathode-first, alternating monophasic stimulation for the reliable suppression of stimulus artifact (pulse repetition frequency: 5 Hz). Results from right cervical VNS experiments in anesthetized rats showed that both the fractal and the circular electrodes can recruit small, myelinated Ad and B fibers to a similar degree (pulse amplitude: 0-0.4 mA, pulse width: 0.1 ms) (Figure 1.), but fractal electrodes produce a more uniform and consistent fiber recruitment profile (Figure 2.). We observed volleys within the slow conduction velocity range (< 3 m/s), which we suspect to be signals from the C-fibers. Our next plan is to obtain more experimental data to statistically identify the efficiency of various electrode designs in stimulating small fibers and to investigate the electrical potential profile of these electrodes in a biophysical model.

Selective Vagus Nerve Stimulation as a Therapeutic Approach for the Treatment of ARDS: A Rationale for Neuro-Immunomodulation in COVID-19 Disease.

Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury. It is induced by sepsis, aspiration, and pneumonia, including that caused by SARS coronavirus and human influenza viruses. The main pathophysiological mechanism of ARDS is a systemic inflammatory response. Vagus nerve stimulation (VNS) can limit cytokine production in the spleen and thereby dampen any systemic inflammation and inflammation-induced tissue damage in the lungs and other organs. However, the effects of increased parasympathetic outflow to the lungs when non-selective VNS is applied may result in bronchoconstriction, increased mucus secretion and enhance local pulmonary inflammatory activity; this may outweigh the beneficial systemic anti-inflammatory action of VNS. Organ/function-specific therapy can be achieved by imaging of localized fascicle activity within the vagus nerve and selective stimulation of identified organ-specific fascicles. This may be able to provide selective neuromodulation of different pathways within the vagus nerve and offer a novel means to improve outcome in ARDS. This has motivated this review in which we discuss the mechanisms of anti-inflammatory effects of VNS, progress in selective VNS techniques, and a possible application for ARDS.

Model-based geometrical optimisation and in vivo validation of a spatially selective multielectrode cuff array for vagus nerve neuromodulation

BackgroundNeuromodulation by electrical stimulation of the human cervical vagus nerve may be limited by adverse side effects due to stimulation of off-target organs. It may be possible to overcome this by spatially selective stimulation of peripheral nerves. Preliminary studies have shown this is possible using a cylindrical multielectrode human-sized nerve cuff in vagus nerve selective neuromodulation. New methodThe model-based optimisation method for multi-electrode geometric design is presented. The method was applied for vagus nerve cuff array and suggested two rings of 14 electrodes, 3 mm apart, with 0.4 mm electrode width and separation and length 0.5−3 mm, with stimulation through a pair in the same radial position on the two rings. The electrodes were fabricated using PDMS-embedded stainless steel foil and PEDOT: pTS coating. ResultsIn the cervical vagus nerve in anaesthetised sheep, it was possible to selectively reduce the respiratory breath rate (RBR) by 85 ± 5% without affecting heart rate, or selectively reduce heart rate (HR) by 20 ± 7% without affecting respiratory rate. The cardiac- and pulmonary-specific sites on the nerve cross-sectional perimeter were localised with a radial separation of 105 ± 5 degrees (P < 0.01, N = 24 in 12 sheep). ConclusionsResults suggest organotopic or function-specific organisation of neural fibres in the cervical vagus nerve. The optimised electrode array demonstrated selective electrical neuromodulation without adverse side effects. It may be possible to translate this to improved treatment by electrical autonomic neuromodulation for currently intractable conditions.

Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat.

It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness. The human and pig VNs were comparable sizes (∼2 mm cervically; ∼1.6 mm subdiaphragmatically), while the rat nerves were ten times smaller. The pig nerves had ten times more fascicles—and the fascicles were smaller—than in human nerves (47 vs. 7 fascicles cervically; 38 vs. 5 fascicles subdiaphragmatically). Comparing the cervical to the subdiaphragmatic VNs, the nerves and fascicles were larger at the cervical level for all species and there were more fascicles for pigs. Human morphology generally exhibited greater variability across samples than pigs and rats. A prior study of human somatic nerves indicated that the ratio of perineurium thickness to fascicle diameter was approximately constant across fascicle diameters. However, our data found thicker human and pig VN perineurium than those prior data: the VNs had thicker perineurium for larger fascicles and thicker perineurium normalized by fascicle diameter for smaller fascicles. Understanding these differences in VN morphology between preclinical models and the clinical target, as well as the variability across individuals of a species, is essential for designing suitable cuff electrodes and stimulation parameters and for informing translation of preclinical results to clinical application to advance the therapeutic efficacy of VNS.