Simultaneous decoding of cardiovascular and respiratory functional changes from pig intraneural vagus nerve signals.

Objective. Bioelectronic medicine is opening new perspectives for the treatment of some major chronic diseases through the physical modulation of autonomic nervous system activity. Being the main peripheral route for electrical signals between central nervous system and visceral organs, the vagus nerve (VN) is one of the most promising targets. Closed-loop VN stimulation (VNS) would be crucial to increase effectiveness of this approach. Therefore, the extrapolation of useful physiological information from VN electrical activity would represent an invaluable source for single-target applications. Here, we present an advanced decoding algorithm novel to VN studies and properly detecting different functional changes from VN signals.Approach. VN signals were recorded using intraneural electrodes in anaesthetized pigs during cardiovascular and respiratory challenges mimicking increases in arterial blood pressure, tidal volume and respiratory rate. We developed a decoding algorithm that combines discrete wavelet transformation, principal component analysis, and ensemble learning made of classification trees.Main results. The new decoding algorithm robustly achieved high accuracy levels in identifying different functional changes and discriminating among them. Interestingly our findings suggest that electrodes positioning plays an important role on decoding performances. We also introduced a new index for the characterization of recording and decoding performance of neural interfaces. Finally, by combining an anatomically validated hybrid neural model and discrimination analysis, we provided new evidence suggesting a functional topographical organization of VN fascicles.Significance. This study represents an important step towards the comprehension of VN signaling, paving the way for the development of effective closed-loop VNS systems.

All-Polymer Printed Low-Cost Regenerative Nerve Cuff Electrodes.

Neural regeneration after lesions is still limited by several factors and new technologies are developed to address this issue. Here, we present and test in animal models a new regenerative nerve cuff electrode (RnCE). It is based on a novel low-cost fabrication strategy, called "Print and Shrink", which combines the inkjet printing of a conducting polymer with a heat-shrinkable polymer substrate for the development of a bioelectronic interface. This method allows to produce miniaturized regenerative cuff electrodes without the use of cleanroom facilities and vacuum based deposition methods, thus highly reducing the production costs. To fully proof the electrodes performance in vivo we assessed functional recovery and adequacy to support axonal regeneration after section of rat sciatic nerves and repair with RnCE. We investigated the possibility to stimulate the nerve to activate different muscles, both in acute and chronic scenarios. Three months after implantation, RnCEs were able to stimulate regenerated motor axons and induce a muscular response. The capability to produce fully-transparent nerve interfaces provided with polymeric microelectrodes through a cost-effective manufacturing process is an unexplored approach in neuroprosthesis field. Our findings pave the way to the development of new and more usable technologies for nerve regeneration and neuromodulation.

Ultrasound Stimulations Induce Prolonged Depolarization and Fast Action Potentials in Leech Neurons.

Objective: Ultrasound (US) stimulation carries the promise of a selective, reversible, and non-invasive modulation of neural activity without the need for genetic manipulation of neural structures. However, the mechanisms of US-induced generation of action potentials (APs) are still unclear. Methods: Here we address this issue by analyzing intracellularly recorded responses of leech nociceptive neurons to controlled delivery of US. Results: US induced a depolarization linearly accumulating in time and outlasting the duration of the stimulation. Spiking activity was reliably induced for an optimal US intensity range. Moreover, we found that APs induced by US differ in smaller amplitude and faster repolarization from those induced by electrical stimulation in the same cell but display the same repolarization rate. Conclusions: These results shed light on the mechanism by which spikes are induced by US and pave the way for designing more efficient US stimulation patterns.

Spatially selective activation of the visual cortex via intraneural stimulation of the optic nerve.

Retinal prostheses can restore a functional form of vision in patients affected by dystrophies of the outer retinal layer. Beyond clinical utility, prostheses for the stimulation of the optic nerve, the visual thalamus or the visual cortex could also serve as tools for studying the visual system. Optic-nerve stimulation is particularly promising because it directly activates nerve fibres, takes advantage of the high-level information processing occurring downstream in the visual pathway, does not require optical transparency and could be effective in cases of eye trauma. Here we show, in anaesthetized rabbits and with support from numerical modelling, that an intraneural electrode array with high mechanical stability placed in the intracranial segment of the optic nerve induces, on electrical stimulation, selective activation patterns in the visual cortex. These patterns are measured as electrically evoked cortical potentials via an ECoG array placed in the contralateral cortex. The intraneural electrode array should enable further investigations of the effects of electrical stimulation in the visual system and could be further developed as a visual prosthesis for blind patients.

Implantable Neural Interfaces and Wearable Tactile Systems for Bidirectional Neuroprosthetics Systems.

Neuroprosthetics and neuromodulation represent a promising field for several related applications in the central and peripheral nervous system, such as the treatment of neurological disorders, the control of external robotic devices, and the restoration of lost tactile functions. These actions are allowed by the neural interface, a miniaturized implantable device that most commonly exploits electrical energy to fulfill these operations. A neural interface must be biocompatible, stable over time, low invasive, and highly selective; the challenge is to develop a safe, compact, and reliable tool for clinical applications. In case of anatomical impairments, neuroprosthetics is bound to the need of exploring the surrounding environment by fast-responsive and highly sensitive artificial tactile sensors that mimic the natural sense of touch. Tactile sensors and neural interfaces are closely interconnected since the readouts from the first are required to convey information to the neural implantable apparatus. The role of these devices is pivotal hence technical improvements are essential to ensure a secure system to be eventually adopted in daily life. This review highlights the fundamental criteria for the design and microfabrication of neural interfaces and artificial tactile sensors, their use in clinical applications, and future enhancements for the release of a second generation of devices.

Soft Hydrogel Zwitterionic Coatings Minimize Fibroblast and Macrophage Adhesion on Polyimide Substrates.

Minimizing the foreign body reaction to polyimide-based implanted devices plays a pivotal role in several biomedical applications. In this work, we propose materials exhibiting nonbiofouling properties and a Young's modulus reflecting that of soft human tissues. We describe the synthesis, characterization, and in vitro validation of poly(carboxybetaine) hydrogel coatings covalently attached to polyimide substrates via a photolabile 4-azidophenyl group, incorporated in poly(carboxybetaine) chains at two concentrations of 1.6 and 3.1 mol %. The presence of coatings was confirmed by attenuated total reflectance Fourier transform infrared spectroscopy. White light interferometry was used to evaluate the coating continuity and thickness (between 3 and 6 µm under dry conditions). Confocal laser scanning microscopy allowed us to quantify the thickness of the swollen hydrogel coatings that ranged between 13 and 32 µm. The different hydrogel formulations resulted in stiffness values ranging from 2 to 19 kPa and led to different fibroblast and macrophage responses in vitro. Both cell types showed a minimum adhesion on the softest hydrogel type. In addition, both the overall macrophage activation and cytotoxicity were observed to be negligible for all of the tested material formulations. These results are a promising starting point toward future advanced implantable systems. In particular, such technology paves the way for novel neural interfaces able to minimize the fibrotic reaction, once implanted in vivo, and to maximize their long-term stability and functionality.

Correlation between muscular and nerve signals responsible for hand grasping in non-human primates.

Neuroprosthetic devices that interface with the nervous system to restore functional motor activity offer a viable alternative to nerve regeneration, especially in proximal nerve injuries like brachial plexus injuries where muscle atrophy may set in before nerve re-innervation occurs. Prior studies have used control signals from muscle or cortical activity. However, nerve signals are preferred in many cases since they permit more natural and precise control when compared to muscle activity, and can be accessed with much lower risk than cortical activity. Identification of nerve signals that control the appropriate muscles is essential for the development of such a `bionic link'. Here we examine the correlation between muscle and nerve signals responsible for hand grasping in the M. fascicularis. Simultaneous recordings were performed using a 4-channel thin-film longitudinal intra-fascicular electrode (tf-LIFE) and 9 bipolar endomysial muscle electrodes while the animal performed grasping movements. We were able to identify a high degree of correlation (r > 0.6) between nerve signals from the median nerve and movement-dependent muscle activity from the flexor muscles of the forearm, with a delay that corresponded to 25 m/s nerve conduction velocity. The phase of the flexion could be identified using a wavelet approximation of the ENG. This result confirms this approach for a future neuroprosthetic device for the treatment of peripheral nerve injuries.

Modelization of a self-opening peripheral neural interface: a feasibility study.

In this paper a self-opening intrafascicular neural interface (SELINE) has been modeled using both a theoretical approach and a Finite Element (FE) analysis. This innovative self opening interface has several potential advantages such as: higher selectivity due to its three-dimensional structure and efficient anchorage system. Mechanical, structural and micro-technological issues have been considered to obtain an effective design of the electrode, as a feasibility study of the self-opening approach. A simple framework has been provided to model the insertion and partial retraction into peripheral nerves, resulting in the opening of wings. This integrated approach results in a rational procedure to optimize kinematics, geometry, and structural properties of peripheral interfaces. The design and feasibility study carried out in this work can potentially assure a correct behavior and dimensioning of the neural interface: in this way anomalous breakage should be avoided while mechanical and geometrical biocompatibility should increase.