New Stimulation Device to Drive Multiple Transverse Intrafascicular Electrodes and Achieve Highly Selective and Rich Neural Responses.

Peripheral Nerve Stimulation (PNS) is a promising approach in functional restoration following neural impairments. Although it proves to be advantageous in the number of implantation sites provided compared with intramuscular or epimysial stimulation and the fact that it does not require daily placement, as is the case with surface electrodes, the further advancement of PNS paradigms is hampered by the limitation of spatial selectivity due to the current spread and variations of nerve physiology. New electrode designs such as the Transverse Intrafascicular Multichannel Electrode (TIME) were proposed to resolve this issue, but their use was limited by a lack of innovative multichannel stimulation devices. In this study, we introduce a new portable multichannel stimulator-called STIMEP-and implement different stimulation protocols in rats to test its versatility and unveil the potential of its combined use with TIME electrodes in rehabilitation protocols. We developed and tested various stimulation paradigms in a single fascicle and thereafter implanted two TIMEs. We also tested its stimulation using two different waveforms. The results highlighted the versatility of this new stimulation device and advocated for the parameterizing of a hyperpolarizing phase before depolarization as well as the use of small pulse widths when stimulating with multiple electrodes.

Six-Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback.

OBJECTIVE: Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. METHODS: To this aim, we performed a 6-month clinical study with 3 transradial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. RESULTS: All subjects, notwithstanding their important clinical differences, reported stimulation-induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. INTERPRETATION: The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. ANN NEUROL 2019;85:137-154.

Sensitivity to temporal parameters of intraneural tactile sensory feedback.

BACKGROUND: Recent studies have shown that neural stimulation can be used to provide artificial sensory feedback to amputees eliciting sensations referred on the amputated hand. The temporal properties of the neural stimulation modulate aspects of evoked sensations that can be exploited in a bidirectional hand prosthesis. METHODS: We previously collected evidence that the derivative of the amplitude of the stimulation (intra-digit temporal dynamics) allows subjects to recognize object compliance and that the time delay among stimuli injected through electrodes implanted in different nerves (inter-digit temporal distance) allows to recognize object shapes. Nevertheless, a detailed characterization of the subjects' sensitivity to variations of intra-digit temporal dynamic and inter-digit temporal distance of the intraneural tactile feedback has not been executed. An exhaustive understanding of the overall potentials and limits of intraneural stimulation to deliver sensory feedback is of paramount importance to bring this approach closer and closer to the natural situation. To this aim, here we asked two trans-radial amputees to identify stimuli with different temporal characteristics delivered to the same active site (intra-digit temporal Dynamic Recognition (DR)) or between two active sites (inter-digit Temporal distance Recognition (TR)). Finally, we compared the results achieved for (simulated) TR with conceptually similar experiments with real objects with one subject. RESULTS: We found that the subjects were able to identify stimuli with temporal differences (perceptual thresholds) larger than 0.25 s for DR and larger than 0.125 s for TR, respectively. Moreover, we also found no statistically significant differences when the subjects were asked to identify three objects during simulated 'open-loop' TR experiments or real 'closed-loop' tests while controlling robotic hand. CONCLUSIONS: This study is a new step towards a more detailed analysis of the overall potentials and limits of intraneural sensory feedback. A full characterization is necessary to develop more advanced prostheses capable of restoring all lost functions and of being perceived more as a natural limb by users.

Highly Porous Platinum Electrodes for Dry Ear-EEG Measurements.

The interest in dry electroencephalography (EEG) electrodes has increased in recent years, especially as everyday suitability earplugs for measuring drowsiness or focus of auditory attention. However, the challenge is still the need for a good electrode material, which is reliable and can be easily processed for highly personalized applications. Laser processing, as used here, is a fast and very precise method to produce personalized electrode configurations that meet the high requirements of in-ear EEG electrodes. The arrangement of the electrodes on the flexible and compressible mats allows an exact alignment to the ear mold and contributes to high wearing comfort, as no edges or metal protrusions are present. For better transmission properties, an adapted coating process for surface enlargement of platinum electrodes is used, which can be controlled precisely. The resulting porous platinum-copper alloy is chemically very stable, shows no exposed copper residues, and enlarges the effective surface area by 40. In a proof-of-principle experiment, these porous platinum electrodes could be used to measure the Berger effect in a dry state using just one ear of a test person. Their signal-to-noise ratio and the frequency transfer function is comparable to gel-based silver/silver chloride electrodes.

It's the little things: On the complexity of planar electrode heating in MRI.

Neurological disorders are increasingly analysed and treated with implantable electrodes, and patients with such electrodes are studied with MRI despite the risk of radio-frequency (RF) induced heating during the MRI exam. Recent clinical research suggests that electrodes with smaller diameters of the electrical interface between implant and tissue are beneficial; however, the influence of this electrode contact diameter on RF-induced heating has not been investigated. In this work, electrode contact diameters between 0.3 and 4 mm of implantable electrodes appropriate for stimulation and electrocorticography were evaluated in a 1.5 T MRI system. In situ temperature measurements adapted from the ASTM standard test method were performed and complemented by simulations of the specific absorption rate (SAR) to assess local SAR values, temperature increase and the distribution of dissipated power. Measurements showed temperature changes between 0.8 K and 53 K for different electrode contact diameters, which is well above the legal limit of 1 K. Systematic errors in the temperature measurements are to be expected, as the temperature sensors may disturb the heating pattern near small electrodes. Compared to large electrodes, simulations suggest that small electrodes are subject to less dissipated power, but more localized power density. Thus, smaller electrodes might be classified as safe in current certification procedures but may be more likely to burn adjacent tissue. To assess these local heating phenomena, smaller temperature sensors or new non-invasive temperature sensing methods are needed.

A Novel Approach To Quantify Air-Water Gas Exchange in Shallow Surface Waters Using High-Resolution Time Series of Dissolved Atmospheric Gases.

Gas exchange across the air-water interface is a key process determining the release of greenhouse gases from surface waters and a fundamental component of gas dynamics in aquatic systems. To experimentally quantify the gas transfer velocity in a wide range of aquatic settings, a novel method based on recently developed techniques for the in situ, near-continuous measurement of dissolved (noble) gases with a field portable mass spectrometer is presented. Variations in observed dissolved gas concentrations are damped and lagged with respect to equilibrium concentrations, being the result of (a) temperature (and thus solubility) variations, (b) water depth, and (c) the specific gas transfer velocity ( ki). The method fits a model to the measured gas concentrations to derive the gas transfer velocity from the amplitude and the phase lag between observed and equilibrium concentrations. With the current experimental setup, the method is sensitive to gas transfer velocities of 0.05-9 m/day (for N2), at a water depth of 1 m, and a given daily water temperature variation of 10 °C. Experiments were performed (a) in a controlled experiment to prove the concept and to confirm the capability to determine low transfer velocities and (b) in a field study in a shallow coastal lagoon covering a range of transfer velocities, demonstrating the field applicability of the method.

Neuromuscular adaptations and sensorimotor integration following a unilateral transfemoral amputation.

BACKGROUND: Following an amputation, the human postural control system develops neuromuscular adaptations to regain an effective postural control. We investigated the compensatory mechanisms behind these adaptations and how sensorimotor integration is affected after a lower-limb transfemoral amputation. METHODS: Center of pressure (CoP) data of 12 unilateral transfemoral amputees and 12 age-matched able-bodied subjects were recorded during quiet standing with eyes open (EO) and closed (EC). CoP adjustments under each leg were recorded to study their contribution to posture control. The spatial structure of the CoP displacements was characterized by measuring the mean distance, the mean velocity of the CoP adjustments, and the sway area. The Entropic Half-Life (EnHL) quantifies the temporal structure of the CoP adjustments and was used to infer disrupted sensory feedback loops in amputees. We expanded the analysis with measures of weight-bearing imbalance and asymmetry, and with two standardized balance assessments, the Berg Balance Scale (BBS) and Timed Up-and-Go (TUG). RESULTS: There was no difference in the EnHL values of amputees and controls when combining the contributions of both limbs (p = 0.754). However, amputees presented significant differences between the EnHL values of the intact and prosthetic limb (p <  0.001). Suppressing vision reduced the EnHL values of the intact (p = 0.001) and both legs (p = 0.028), but not in controls. Vision feedback in amputees also had a significant effect (increase) on the mean CoP distance (p <  0.001), CoP velocity (p <  0.001) and sway area (p = 0.007). Amputees presented an asymmetrical stance. The EnHL values of the intact limb in amputees were positively correlated to the BBS scores (EO: ρ = 0.43, EC: ρ = 0.44) and negatively correlated to the TUG times (EO: ρ = - 0.59, EC: ρ = - 0.69). CONCLUSION: These results suggest that besides the asymmetry in load distribution, there exist neuromuscular adaptations after an amputation, possibly related to the loss of sensory feedback and an altered sensorimotor integration. The EnHL values suggest that the somatosensory system predominates in the control of the intact leg. Further, suppressing the visual system caused instability in amputees, but had a minimal impact on the CoP dynamics of controls. These findings points toward the importance of providing somatosensory feedback in lower-limb prosthesis to reestablish a normal postural control. TRIAL REGISTRATION: DRKS00015254 , registered on September 20th, 2018.

Developing Next-generation Brain Sensing Technologies - A Review.

Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients.

Synchrony surfacing: Epicortical recording of correlated action potentials.

Synchronous spiking of multiple neurons is a key phenomenon in normal brain function and pathologies. Recently, approaches to record spikes from the intact cortical surface using small high-density arrays of microelectrodes have been reported. It remained unaddressed how epicortical spiking relates to intracortical unit activity. We introduced a mesoscale approach using an array of 64 electrodes with intermediate diameter (250 µm) and combined large-coverage epicortical recordings in ferrets with intracortical recordings via laminar probes. Empirical data and modelling strongly suggest that our epicortical electrodes selectively captured synchronized spiking of neurons in the cortex beneath. As a result, responses to sensory stimulation were more robust and less noisy compared to intracortical activity, and receptive field properties were well preserved in epicortical recordings. This should promote insights into assembly-coding beyond the informative value of subdural EEG or single-unit spiking, and be advantageous to real-time applications in brain-machine interfacing.

How to record high-frequency oscillations in epilepsy: A practical guideline.

OBJECTIVE: Technology for localizing epileptogenic brain regions plays a central role in surgical planning. Recent improvements in acquisition and electrode technology have revealed that high-frequency oscillations (HFOs) within the 80-500 Hz frequency range provide the neurophysiologist with new information about the extent of the epileptogenic tissue in addition to ictal and interictal lower frequency events. Nevertheless, two decades after their discovery there remain questions about HFOs as biomarkers of epileptogenic brain and there use in clinical practice. METHODS: In this review, we provide practical, technical guidance for epileptologists and clinical researchers on recording, evaluation, and interpretation of ripples, fast ripples, and very high-frequency oscillations. RESULTS: We emphasize the importance of low noise recording to minimize artifacts. HFO analysis, either visual or with automatic detection methods, of high fidelity recordings can still be challenging because of various artifacts including muscle, movement, and filtering. Magnetoencephalography and intracranial electroencephalography (iEEG) recordings are subject to the same artifacts. SIGNIFICANCE: High-frequency oscillations are promising new biomarkers in epilepsy. This review provides interested researchers and clinicians with a review of current state of the art of recording and identification and potential challenges to clinical translation.

Intracortical polyimide electrodes with a bioresorbable coating.

Polyimide based shaft electrodes were coated with a bioresorbable layer to stiffen them for intracortical insertion and to reduce the mechanical mismatch between the target tissue and the implanted device after degradation of the coating. Molten saccharose was used as coating material. In a proof-of-concept study, the electrodes were implanted into the cortex of Wistar rats and the insertion forces during implantation were recorded. Electrochemical impedance spectroscopy was performed immediately after implantation and up to 13 weeks after implantation to monitor the tissue response to the implanted electrodes. The recorded spectra were modeled with an equivalent circuit to differentiate the influence of the single components. In one rat, a peak in the encapsulation resistance was observable after two weeks of implantation, indicating the peak of the acute inflammatory response. In another rat, the lowest resistances were observed after four weeks, indicating the termination of the acute inflammatory response. Multiunit activity was recorded with an adequate signal to noise ratio to allow spike sorting. Histology was performed after 7, 45 and 201 days of implantation. The results showed the highest tissue reaction after 45 days and confirmed impedance data that acute inflammatory reactions terminate over time.

Concept and Development of an Electronic Framework Intended for Electrode and Surrounding Environment Characterization In Vivo.

There has been substantial progress over the last decade towards miniaturizing implantable microelectrodes for use in Active Implantable Medical Devices (AIMD). Compared to the rapid development and complexity of electrode miniaturization, methods to monitor and assess functional integrity and electrical functionality of these electrodes, particularly during long term stimulation, have not progressed to the same extent. Evaluation methods that form the gold standard, such as stimulus pulse testing, cyclic voltammetry and electrochemical impedance spectroscopy, are either still bound to laboratory infrastructure (impractical for long term in vivo experiments) or deliver no comprehensive insight into the material's behaviour. As there is a lack of cost effective and practical predictive measures to understand long term electrode behaviour in vivo, material investigations need to be performed after explantation of the electrodes. We propose the analysis of the electrode and its environment in situ, to better understand and correlate the effects leading to electrode failure. The derived knowledge shall eventually lead to improved electrode designs, increased electrode functionality and safety in clinical applications. In this paper, the concept, design and prototyping of a sensor framework used to analyse the electrode's behaviour and to monitor diverse electrode failure mechanisms, even during stimulation pulses, is presented. We focused on the electronic circuitry and data acquisition techniques required for a conceptual multi-sensor system. Functionality of single modules and a prototype framework have been demonstrated, but further work is needed to convert the prototype system into an implantable device. In vitro studies will be conducted first to verify sensor performance and reliability.

Influence of Clonidine on Antihypertensive Selective Afferent Vagal Nerve Stimulation in Rats.

OBJECTIVE: Selective-afferent vagal nerve stimulation (sVNS) may be a treatment option for therapy-resistant hypertension, as it lowers blood pressure (BP) in rats without causing significant side effects. Alpha-2-agonists are widely used for the treatment of withdrawal, chronic pain and other disorders, and even if sVNS becomes a treatment option for therapy resistant hypertension, in some patients it might be necessary to combine sVNS with an alpha-2-agonist like clonidine. Alpha-2-agonists exhibit a central and peripheral mechanism of action. This study investigated the influence of the commonly used alpha-2-agonist clonidine on sVNS. MATERIALS AND METHODS: A polyimide multichannel-cuff-electrode was placed around the left vagal nerve bundle including the aortic depressor nerve (ADN) in eight male Wistar rats for the focused stimulation of baroreceptive fibers of the ADN. Stimulation parameters were adapted to the thresholds of the individual animals and ranged from frequencies between 30 and 50 Hz, amplitudes of 0.5-0.9 mA and pulse widths between 0.4 and 0.8 ms. BP was recorded using a microtip transducer in the left carotid artery, and electrocardiography was registered using subcutaneous needle electrodes. RESULTS: Before clonidine, we found a frequency-dependent drop of BP with maximum at 40 Hz. The animals' mean arterial blood pressures and respiration rate dropped after intravenous clonidine administration (10 µg/kg bodyweight), and sVNS still decreased in BP, but they did so to a lesser extent. Unwanted bradycardia, which was expected by the superimposition of sVNS and clonidine, did not occur. Left-sided vagotomy abolished the respiratory depressant effect of clonidine and blunted the BP reducing effect of sVNS while sVNS hardly affected heart rate anymore. CONCLUSIONS: The effect of sVNS on BP is dampened by clonidine, but sVNS can still lower the BP in clonidine treated rats without causing significant bradycardia.

Subchronic stimulation performance of transverse intrafascicular multichannel electrodes in the median nerve of the Göttingen minipig.

This work evaluated the subchronic stimulation performance of an intraneural multichannel electrode (transverse intrafascicular multichannel electrode, TIME) in a large human-sized nerve. One or two TIMEs were implanted in the right median nerve above the elbow joint in four pigs for a period of 32 to 37 days (six TIMEs in total). The ability of the contact sites to recruit five muscles in the forelimb was assessed via their evoked electromyographic responses. Based on these responses, a selectivity index was defined. Four TIMEs were able to selectively recruit a subset of muscles throughout the implantation period. The required recruitment current significantly increased, while there was a tendency for the recruitment selectivity to decrease over time. Histological assessment showed that all TIMEs remained inside the nerve and that they were located between fascicles. The average thickness of the encapsulation of the electrode was estimated to be 115.4 ± 51.5 µm (mean ± SD). This study demonstrates the feasibility of keeping the TIME electrodes fixed and functional inside a large polyfascicular human-sized nerve in a subchronic setting.

Towards ultrasound wearable technology for cardiovascular monitoring: from device development to clinical validation.

The advent of flexible, compact, energy-efficient, robust, and user-friendly wearables has significantly impacted the market growth, with an estimated value of 61.30 billion USD in 2022. Wearable sensors have revolutionized in-home health monitoring by warranting continuous measurements of vital parameters. Ultrasound is used to non-invasively, safely, and continuously record vital parameters. The next generation of smart ultrasonic devices for healthcare integrates microelectronics with flexible, stretchable patches and body-conformable devices. They offer not only wearability, and user comfort, but also higher tracking accuracy of immediate changes of cardiovascular parameters. Moreover, due to the fixed adhesion to the skin, errors derived from probe placement or patient movement are mitigated, even though placement at the correct anatomical location is still critical and requires a user's skill and knowledge. In this review, the steps required to bring wearable ultrasonic systems into the medical market (technologies, device development, signal-processing, in-lab validation, and, finally, clinical validation) are discussed. The next generation of vascular ultrasound and its future research directions offer many possibilities for modernizing vascular health assessment and the quality of personalized care for home and clinical monitoring.

Fabrication and Characterization of PDMS Waveguides for Flexible Optrodes.

With the growth of optogenetic research, the demand for optical probes tailored to specific applications is ever rising. Specifically, for applications like the coiled cochlea of the inner ear, where planar, stiff, and nonconformable probes can hardly be used, transitioning from commonly used stiff glass fibers to flexible probes is required, especially for long-term use. Following this demand, polydimethylsiloxane (PDMS) with its lower Young's modulus compared to glass fibers can serve as material of choice. Hence, the long-term usability of PDMS as a waveguide material with respect to variations in transmission and refractive index over time is investigated. Different manufacturing methods for PDMS-based flexible waveguides are established and compared with the aim to minimize optical losses and thus maximize optical output power. Finally, the waveguides with lowest optical losses (-4.8 dB cm-1 ± 1.3 dB cm-1 at 472 nm) are successfully inserted into the optogenetically modified cochlea of a Mongolian gerbil (Meriones unguiculatus), where optical stimuli delivered by the waveguides evoked robust neuronal responses in the auditory pathway.

Recording Quality Is Systematically Related to Electrode Impedance.

Extracellular recordings with planar microelectrodes are the gold standard technique for recording the fast action potentials of neurons in the intact brain. The introduction of microfabrication techniques has revolutionized the in vivo recording of neuronal activity and introduced high-density, multi-electrode arrays that increase the spatial resolution of recordings and the number of neurons that can be simultaneously recorded. Despite these innovations, there is still debate about the ideal electrical transfer characteristics of extracellular electrodes. This uncertainty is partly due to the lack of systematic studies comparing electrodes with different characteristics, particularly for chronically implanted arrays over extended time periods. Here a high-density, flexible, and thin-film array is fabricated and tested, containing four distinct electrode types differing in surface material and surface topology and, thus, impedance. It is found that recording quality is strongly related to electrode impedance with signal amplitude and unit yield negatively correlated to impedance. Electrode impedances are stable for the duration of the experiment (up to 12 weeks) and recording quality does not deteriorate. The findings support the expectation from the theory that recording quality will increase as impedance decreases.

Biomimetic computer-to-brain communication enhancing naturalistic touch sensations via peripheral nerve stimulation.

Artificial communication with the brain through peripheral nerve stimulation shows promising results in individuals with sensorimotor deficits. However, these efforts lack an intuitive and natural sensory experience. In this study, we design and test a biomimetic neurostimulation framework inspired by nature, capable of "writing" physiologically plausible information back into the peripheral nervous system. Starting from an in-silico model of mechanoreceptors, we develop biomimetic stimulation policies. We then experimentally assess them alongside mechanical touch and common linear neuromodulations. Neural responses resulting from biomimetic neuromodulation are consistently transmitted towards dorsal root ganglion and spinal cord of cats, and their spatio-temporal neural dynamics resemble those naturally induced. We implement these paradigms within the bionic device and test it with patients (ClinicalTrials.gov identifier NCT03350061). He we report that biomimetic neurostimulation improves mobility (primary outcome) and reduces mental effort (secondary outcome) compared to traditional approaches. The outcomes of this neuroscience-driven technology, inspired by the human body, may serve as a model for advancing assistive neurotechnologies.

NeuroBus - Architecture for an Ultra-Flexible Neural Interface.

This article presents the system architecture for an implant concept called NeuroBus. Tiny distributed direct digitizing neural recorder ASICs on an ultra-flexible polyimide substrate are connected in a bus-like structure, allowing short connections between electrode and recording front-end with low wiring effort and high customizability. The small size (344 µm × 294 µm) of the ASICs and the ultraflexible substrate allow a low bending stiffness, enabling the implant to adapt to the curvature of the brain and achieving high structural biocompatibility. We introduce the architecture, the integrated building blocks, and the post-CMOS processes required to realize a NeuroBus, and we characterize the prototyped direct digitizing neural recorder front-end as well as polyimide-based ECoG brain interface. A rodent animal model is further used to validate the joint capability of the recording front-end and thin-film electrode array.