The effects of targeted vagus nerve stimulation on glucose homeostasis in STZ-induced diabetic rodents.

During type 1 diabetes, an autoimmune attack destroys pancreatic ß-cells leading to the inability to maintain glucose homeostasis. These ß-cells are neuroresponsive endocrine cells which normally secrete insulin partially in response to input from the vagus nerve. This neural pathway can be utilized as a point of therapeutic intervention by delivering exogenous stimulation to drive increased insulin secretion. In this study, a cuff electrode was implanted on the pancreatic branch of the vagus nerve just prior to pancreatic insertion in rats, and a continuous glucose meter was implanted into the descending aorta. Streptozotocin (STZ) was used to induce a diabetic state, and changes in blood glucose were assessed using various stimulation parameters. Stimulation driven changes in hormone secretion, pancreatic blood flow, and islet cell populations were assessed. We found increased changes in the rate of blood glucose change during stimulation which subsided after stimulation ended paired with increased concentration of circulating insulin. We did not observe increased pancreatic perfusion, which suggests that the modulation of blood glucose was due to the activation of b-cells rather than changes in the extra-organ transport of insulin. Pancreatic neuromodulation showed potentially protective effects by reducing deficits in islet diameter, and ameliorating insulin loss after STZ treatment.

Environmental Enrichment Sharpens Sensory Acuity by Enhancing Information Coding in Barrel Cortex and Premotor Cortex.

Environmental enrichment (EE) is beneficial to sensory functions. Thus, elucidating the neural mechanism underlying improvement of sensory stimulus discrimination is important for developing therapeutic strategies. We aim to advance the understanding of such neural mechanism. We found that tactile enrichment improved tactile stimulus feature discrimination. The neural correlate of such improvement was revealed by analyzing single-cell information coding in both the primary somatosensory cortex and the premotor cortex of awake behaving animals. Our results show that EE enhances the decision-information coding capacity of cells that are tuned to adjacent whiskers, and of premotor cortical cells.

Designing a bioelectronic treatment for Type 1 diabetes: targeted parasympathetic modulation of insulin secretion.

The pancreas is a visceral organ with exocrine functions for digestion and endocrine functions for maintenance of blood glucose homeostasis. In pancreatic diseases such as Type 1 diabetes, islets of the endocrine pancreas become dysfunctional and normal regulation of blood glucose concentration ceases. In healthy individuals, parasympathetic signaling to islets via the vagus nerve, triggers release of insulin from pancreatic ß-cells and glucagon from α-cells. Using electrical stimulation to augment parasympathetic signaling may provide a way to control pancreatic endocrine functions and ultimately control blood glucose. Historical data suggest that cervical vagus nerve stimulation recruits many visceral organ systems. Simultaneous modulation of liver and digestive function along with pancreatic function provides differential signals that work to both raise and lower blood glucose. Targeted pancreatic vagus nerve stimulation may provide a solution to minimizing off-target effects through careful electrode placement just prior to pancreatic insertion.

Development and validation of an ambulatory piglet model for short bowel syndrome with ileo-colonic anastomosis.

IMPACT STATEMENT: Short bowel syndrome is associated with significant comorbidities and mortality. This study is important as unlike current systems, it provides a validated piglet model which mirrors anatomical, histological, and serological characteristics observed in human SBS. This model can be used to advance knowledge into mechanistic pathways and therapeutic modalities to improve outcomes for SBS patients. This study is novel in that in addition to significant reduction in the remnant bowel and noted liver disease, we also developed a method to emulate ileocecal valve resection and described gut adaptive responses which has important clinical implications in humans.

Enteric Neuromodulation for the Gut and Beyond.

The small intestine is the longest organ in the human body, spanning a length of ∼5 m and compartmentalized into three distinct regions with specific roles in maintenance of comprehensive homeostasis. Along its length exists as a unique and independent system-called the enteric nervous system (ENS)-which coordinates the multitude of functions continuously around the clock. Yet, with so many vital roles played, the functions, relationships, and roles of the small intestine and ENS remain largely elusive. This fundamental hole in the physiology of the small intestine and ENS introduces a substantial number of challenges when attempting to create bioelectronic approaches for treatment of various disorders originating in the small intestine. Here, we review existing therapeutic options for modulating the small intestine, discuss fundamental gaps that must be addressed, and highlight novel methods and approaches to consider for development of bioelectronic approaches aiming to modulate the small intestine.

Percutaneous CT-Guided Cryovagotomy in Patients with Class I or Class II Obesity: A Pilot Trial.

OBJECTIVE: This study evaluated the safety of percutaneous CT-guided cryoablation of the vagus nerve (percutaneous cryovagotomy) in participants with class I or class II obesity. METHODS: The study was an open-label, single-group, prospective pilot investigation designed around safety-related stopping criteria. Twenty participants with 30 > BMI > 37 underwent percutaneous cryovagotomy with follow-up visits at day 7, 45, 90, and 180. Data related to adverse events, technical success, weight loss, quality of life, dietary intake, global impressions of hunger change, activity, and body composition were analyzed. RESULTS: The procedural technical success rate was 100%. There were no adverse events in 19 participants who completed the trial. Ninety-five percent of patients reported decreased appetite following the procedure, and reductions in mean absolute weight and BMI were observed at all time points. The mean quality of life and activity scores improved from baseline to 6 months post procedure, and mean caloric intake and overall body fat decreased over the same period. CONCLUSIONS: Percutaneous CT-guided cryovagotomy is feasible and was tolerated without complications or adverse events in this cohort. Quantitative preliminary data from this pilot investigation inform the design of a larger prospective randomized clinical trial.

Targeted Vagus Nerve Stimulation does not Disrupt Cardiac Function in the Diabetic Rat.

In this study, we acutely identified a target branch of the vagus nerve known as the pancreatic branch of the vagus nerve, which exclusively innervates the pancreas by applying electrical stimulus to the known cervical vagus nerve and observing compound neural action potentials at the target nerve. In a set of chronically implanted rats, the target nerve was again cuffed using an electrode and also implanted with a continuous glucose monitor. A model of type 1 diabetes (T1D) was chemically induced and hyperglycemic state confirmed. After induction, stimulation was applied to the pancreatic branch of the vagus nerve and heart rate variability measured to assess the targeted nature of the stimulation. Pancreatic vagus nerve stimulation in a diabetic model was not found to influence heart rate demonstrating the ability of targeted stimulation to be used as for organ-specific neuromodulation while minimizing side effects.

Challenges associated with nerve conduction block using kilohertz electrical stimulation.

Neuromodulation therapies, which electrically stimulate parts of the nervous system, have traditionally attempted to activate neurons or axons to restore function or alleviate disease symptoms. In stark contrast to this approach is inhibiting neural activity to relieve disease symptoms and/or restore homeostasis. One potential approach is kilohertz electrical stimulation (KES) of peripheral nerves-which enables a rapid, reversible, and localized block of conduction. This review highlights the existing scientific and clinical utility of KES and discusses the technical and physiological challenges that must be addressed for successful translation of KES nerve conduction block therapies.

Kilohertz Electrical Stimulation Nerve Conduction Block: Effects of Electrode Material.

Kilohertz electrical stimulation (KES) has enabled a novel new paradigm for spinal cord and peripheral nerve stimulation to treat a variety of neurological diseases. KES can excite or inhibit nerve activity and is used in many clinical devices today. However, the impact of different electrode materials on the efficacy of KES is unknown. We investigated the effect of different electrode materials and their respective charge injection mechanisms on KES nerve block thresholds using 20- and 40-kHz current-controlled sinusoidal KES waveforms. We evaluated the nerve block threshold and the power requirements for achieving an effective KES nerve block. In addition, we evaluated potential effects on the onset duration and recovery of normal conduction after delivery of KES. We found that thresholds and the onset and recovery of KES nerve block are not a function of the electrode material. In contrast, the power dissipation varies among electrode materials and is a function of the materials' properties at high frequencies. We conclude that materials with a proven track record of chronic stability, both for the tissue and electrode, are suitable for developing KES nerve block therapies.

High-density EEG characterization of brain responses to auditory rhythmic stimuli during wakefulness and NREM sleep.

Auditory rhythmic sensory stimulation modulates brain oscillations by increasing phase-locking to the temporal structure of the stimuli and by increasing the power of specific frequency bands, resulting in Auditory Steady State Responses (ASSR). The ASSR is altered in different diseases of the central nervous system such as schizophrenia. However, in order to use the ASSR as biological markers for disease states, it needs to be understood how different vigilance states and underlying brain activity affect the ASSR. Here, we compared the effects of auditory rhythmic stimuli on EEG brain activity during wake and NREM sleep, investigated the influence of the presence of dominant sleep rhythms on the ASSR, and delineated the topographical distribution of these modulations. Participants (14 healthy males, 20-33 years) completed on the same day a 60 min nap session and two 30 min wakefulness sessions (before and after the nap). During these sessions, amplitude modulated (AM) white noise auditory stimuli at different frequencies were applied. High-density EEG was continuously recorded and time-frequency analyses were performed to assess ASSR during wakefulness and NREM periods. Our analysis revealed that depending on the electrode location, stimulation frequency applied and window/frequencies analysed the ASSR was significantly modulated by sleep pressure (before and after sleep), vigilance state (wake vs. NREM sleep), and the presence of slow wave activity and sleep spindles. Furthermore, AM stimuli increased spindle activity during NREM sleep but not during wakefulness. Thus, (1) electrode location, sleep history, vigilance state and ongoing brain activity needs to be carefully considered when investigating ASSR and (2) auditory rhythmic stimuli during sleep might represent a powerful tool to boost sleep spindles.

Corrigendum: Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.

This corrects the article DOI: 10.1038/srep39810.

Hard real-time closed-loop electrophysiology with the Real-Time eXperiment Interface (RTXI).

The ability to experimentally perturb biological systems has traditionally been limited to static pre-programmed or operator-controlled protocols. In contrast, real-time control allows dynamic probing of biological systems with perturbations that are computed on-the-fly during experimentation. Real-time control applications for biological research are available; however, these systems are costly and often restrict the flexibility and customization of experimental protocols. The Real-Time eXperiment Interface (RTXI) is an open source software platform for achieving hard real-time data acquisition and closed-loop control in biological experiments while retaining the flexibility needed for experimental settings. RTXI has enabled users to implement complex custom closed-loop protocols in single cell, cell network, animal, and human electrophysiology studies. RTXI is also used as a free and open source, customizable electrophysiology platform in open-loop studies requiring online data acquisition, processing, and visualization. RTXI is easy to install, can be used with an extensive range of external experimentation and data acquisition hardware, and includes standard modules for implementing common electrophysiology protocols.

Kilohertz Electrical Stimulation Nerve Conduction Block: Effects of Electrode Surface Area.

Kilohertz electrical stimulation (KES) induces repeatable and reversible conduction block of nerve activity and is a potential therapeutic option for various diseases and disorders resulting from pathological or undesired neurological activity. However, successful translation of KES nerve block to clinical applications is stymied by many unknowns, such as the relevance of the onset response, acceptable levels of waveform contamination, and optimal electrode characteristics. We investigated the role of electrode geometric surface area on the KES nerve block threshold using 20- and 40-kHz current-controlled sinusoidal KES. Electrodes were electrochemically characterized and used to characterize typical KES waveforms and electrode charge characteristics. KES nerve block amplitudes, onset duration, and recovery of normal conduction after delivery of the KES were evaluated along with power requirements for effective KES nerve block. Results from this investigation demonstrate that increasing electrode geometric surface area provides for a more power-efficient KES nerve block. Reductions in block threshold by increased electrode surface area were found to be KES-frequency-dependent, with block thresholds and average power consumption reduced by greater than two times with 20-kHz KES waveforms and greater than three times for 40-kHz KES waveforms.

Open Ephys: an open-source, plugin-based platform for multichannel electrophysiology.

OBJECTIVE: Closed-loop experiments, in which causal interventions are conditioned on the state of the system under investigation, have become increasingly common in neuroscience. Such experiments can have a high degree of explanatory power, but they require a precise implementation that can be difficult to replicate across laboratories. We sought to overcome this limitation by building open-source software that makes it easier to develop and share algorithms for closed-loop control. APPROACH: We created the Open Ephys GUI, an open-source platform for multichannel electrophysiology experiments. In addition to the standard 'open-loop' visualization and recording functionality, the GUI also includes modules for delivering feedback in response to events detected in the incoming data stream. Importantly, these modules can be built and shared as plugins, which makes it possible for users to extend the functionality of the GUI through a simple API, without having to understand the inner workings of the entire application. MAIN RESULTS: In combination with low-cost, open-source hardware for amplifying and digitizing neural signals, the GUI has been used for closed-loop experiments that perturb the hippocampal theta rhythm in a phase-specific manner. SIGNIFICANCE: The Open Ephys GUI is the first widely used application for multichannel electrophysiology that leverages a plugin-based workflow. We hope that it will lower the barrier to entry for electrophysiologists who wish to incorporate real-time feedback into their research.

Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.

Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide-range of inflammatory pathological conditions. In contrast, afferent cVN activation amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines. Ideally, to clinically implement anti-inflammatory therapy via cervical vagus nerve stimulation (cVNS) one should selectively activate the efferent pathway. Unfortunately, current implementations, in animal and clinical investigations, activate both afferent and efferent pathways. We paired cVNS with kilohertz electrical stimulation (KES) nerve block to preferentially activate efferent pathways while blocking afferent pathways. Selective efferent cVNS enhanced the anti-inflammatory effects of cVNS. Our results demonstrate that: (i) afferent, but not efferent, cVNS synchronously activates the GSN in a dose-dependent manner; (ii) efferent cVNS enabled by complete afferent KES nerve block enhances the anti-inflammatory benefits of cVNS; and (iii) incomplete afferent KES nerve block exacerbates systemic inflammation. Overall, these data demonstrate the utility of paired efferent cVNS and afferent KES nerve block for achieving selective efferent cVNS, specifically as it relates to neuromodulation of systemic inflammation.

Limiting Antibiotics When Managing Mandible Fractures May Not Increase Infection Risk.

PURPOSE: To estimate and compare 1) the frequencies of surgical site infections (SSIs) and 2) adverse antibiotic effects (AAEs) between patients who receive only intraoperative antibiotics (study group) and those who receive intraoperative antibiotics plus additional preoperative or postoperative antibiotics (control group) while undergoing operative treatment of open mandibular fractures. MATERIALS AND METHODS: The authors designed a retrospective cohort study and enrolled a sample derived from patients presenting to the Harborview Medical Center from 2009 through 2014 for the management of open mandibular fractures. Eligible patients were at least 18 years of age with open, isolated mandibular fractures treated by open reduction and internal fixation using transoral approaches or closed reduction and intermaxillary fixation. The primary predictor variable was antibiotic exposure. The study group received antibiotics administered within 1 hour before the incision, with possible intraoperative re-dosing, and the control group received antibiotics according to the study group plus preoperative or postoperative antibiotics. The primary outcome was SSI frequency. The secondary outcome was AAE frequency. Univariate, bivariate, and multiple logistic regression analyses were performed. Statistical significance was set at a P value less than or equal to .05. RESULTS: The sample was comprised of 510 patients (mean age, 29 ± 11.4 yr; 86% men). The study group had 58 patients (11%) and the control group had 452 patients (89%). The SSI frequencies in the study and control groups were 9 and 17%, respectively (P = .13). There were 5 (1%) AAEs reported, all in the control group. In the multivariable logistic regression model, only tobacco use was associated with an increased risk for SSI (odds ratio = 2.8; 95% confidence interval, 1.5-5.5; P = .0015). CONCLUSION: Limiting antibiotic exposure to only intraoperative antibiotic prophylaxis in patients undergoing transoral operative treatment of isolated open mandibular fractures was not associated with an increased risk of SSIs.

Microneedle cuff electrodes for extrafascicular peripheral nerve interfacing.

OBJECTIVE: The work presented here describes a new tool for peripheral nerve interfacing, called the microneedle cuff (µN-cuff) electrode. APPROACH: µN arrays are designed and integrated into cuff electrodes for penetrating superficial tissues while remaining non-invasive to delicate axonal tracts. MAIN RESULTS: In acute testing, the presence of 75 µm height µNs decreased the electrode-tissue interface impedance by 0.34 kΩ, resulting in a 0.9 mA reduction in functional stimulation thresholds and increased the signal-to-noise ratio by 9.1 dB compared to standard (needle-less) nerve cuff electrodes. Preliminary acute characterization suggests that µN-cuff electrodes provide the stability and ease of use of standard cuff electrodes while enhancing electrical interfacing characteristics. SIGNIFICANCE: The ability to stimulate, block, and record peripheral nerve activity with greater specificity, resolution, and fidelity can enable more precise spatiotemporal control and measurement of neural circuits.

Differential fiber-specific block of nerve conduction in mammalian peripheral nerves using kilohertz electrical stimulation.

Kilohertz electrical stimulation (KES) has been shown to induce repeatable and reversible nerve conduction block in animal models. In this study, we characterized the ability of KES stimuli to selectively block specific components of stimulated nerve activity using in vivo preparations of the rat sciatic and vagus nerves. KES stimuli in the frequency range of 5-70 kHz and amplitudes of 0.1-3.0 mA were applied. Compound action potentials were evoked using either electrical or sensory stimulation, and block of components was assessed through direct nerve recordings and muscle force measurements. Distinct observable components of the compound action potential had unique conduction block thresholds as a function of frequency of KES. The fast component, which includes motor activity, had a monotonically increasing block threshold as a function of the KES frequency. The slow component, which includes sensory activity, showed a nonmonotonic block threshold relationship with increasing KES frequency. The distinct trends with frequency of the two components enabled selective block of one component with an appropriate choice of frequency and amplitude. These trends in threshold of the two components were similar when studying electrical stimulation and responses of the sciatic nerve, electrical stimulation and responses of the vagus nerve, and sensorimotor stimulation and responses of the sciatic nerve. This differential blocking effect of KES on specific fibers can extend the applications of KES conduction block to selective block and stimulation of neural signals for neuromodulation as well as selective control of neural circuits underlying sensorimotor function.

A robust nickel catalyst for cyanomethylation of aldehydes: activation of acetonitrile under base-free conditions.

Nick of time: The nickel cyanomethyl complex 1 catalyzes the room temperature coupling of aldehydes with acetonitrile under base-free conditions. The catalytic system is long-lived and remarkably efficient with high turnover numbers (TONs) and turnover frequencies (TOFs) achieved. The mild reaction conditions allow a wide variety of aldehydes, including base-sensitive ones, to catalytically react with acetonitrile.

Pincer-ligated nickel hydridoborate complexes: the dormant species in catalytic reduction of carbon dioxide with boranes.

Nickel pincer complexes of the type [2,6-(R(2)PO)(2)C(6)H(3)]NiH (R = (t)Bu, 1a; R = (i)Pr, 1b; R = (c)Pe, 1c) react with BH(3)·THF to produce borohydride complexes [2,6-(R(2)PO)(2)C(6)H(3)]Ni(η(2)-BH(4)) (2a-c), as confirmed by NMR and IR spectroscopy, X-ray crystallography, and elemental analysis. The reactions are irreversible at room temperature but reversible at 60 °C. Compound 1a exchanges its hydrogen on the nickel with the borane hydrogen of 9-BBN or HBcat, but does not form any observable adduct. The less bulky hydride complexes 1b and 1c, however, yield nickel dihydridoborate complexes reversibly at room temperature when mixed with 9-BBN and HBcat. The dihydridoborate ligand in these complexes adopts an η(2)-coordination mode, as suggested by IR spectroscopy and X-ray crystallography. Under the catalytic influence of 1a-c, reduction of CO(2) leads to the methoxide level when 9-BBN or HBcat is employed as the reducing agent. The best catalyst, 1a, involves bulky substituents on the phosphorus donor atoms. Catalytic reactions involving 1b and 1c are less efficient because of the formation of dihydridoborate complexes as the dormant species as well as partial decomposition of the catalysts by the boranes.