Assessment of the Factors Influencing the Recording Performance of Circumneural Electrodes.

The quality of recorded peripheral nerve signals is decisive for their application in therapies. The electroneurogram can be recorded via implantable circumeural electrodes that are wrapped around the peripheral nerve. The shape and amplitude of the signal recorded by the electrode are influenced by the design and contact configuration of the electrode. In this paper, the impact of the number of contacts, contact size and electrical insulation to the outside is investigated to predict the single fiber action potential based on the measured impedance data.

Biological Impact on the Stability and Reliability of Acute and Chronic Platinum based Thin Film Neural Interfaces in Vivo.

Reliability, stability and biocompatibility of an im-plant are the keys to transferring a preclinical study into the re-ality of clinical applications for diagnostics and therapy of pa-tients. Amongst the smallest and most critical components of neuroprostheses are the neural interfaces to the tissue. These could be seen as the most functional and yet most sensitive parts to connect to and interact with the nervous system. Thin film systems in the submicro- to nanometers range with a high num-ber of channels record biological signals and excite nerves aspiring high spatial sensitivity at the scale of few neurons. The im-pairments of the technical material caused by the harsh environ-ment of the human body and potential damage to the tissue by the foreign body state the greatest obstacle to overcome. Here, we present an analysis on impact of acutely and chronically im-planted subdural electrocorticography (ECoG) recording arrays on the neural tissue and the accompanied material failure mechanisms of the thin film neural interfaces in vivo.

Bidirectional bionic limbs: a perspective bridging technology and physiology.

Precise control of bionic limbs relies on robust decoding of motor commands from nerves or muscles signals and sensory feedback from artificial limbs to the nervous system by interfacing the afferent nerve pathways. Implantable devices for bidirectional communication with bionic limbs have been developed in parallel with research on physiological alterations caused by an amputation. In this perspective article, we question whether increasing our effort on bridging these technologies with a deeper understanding of amputation pathophysiology and human motor control may help to overcome pressing stalls in the next generation of bionic limbs.

Unilateral transfemoral amputees exhibit altered strength and dynamics of muscular co-activation modulated by visual feedback.

Objective.Somatosensory perception is disrupted in patients with a lower limb amputation. This increases the difficulty to maintain balance and leads to the development of neuromuscular adjustments. We investigated how these adjustments are reflected in the co-activation of lower body muscles and are modulated by visual feedback.Approach.We measured electromyography (EMG) signals of muscles from the trunk (erector spinae and obliquus external), and the lower intact/dominant leg (tibialis anterior and medial gastrocnemius) in 11 unilateral transfemoral amputees and 11 age-matched able-bodied controls during 30 s of upright standing with and without visual feedback. Muscle synergies involved in balance control were investigated using wavelet coherence analysis. We focused on seven frequencies grouped in three frequency bands, a low-frequency band (7.56 and 19.86 Hz) representing more sub-cortical and spinal inputs to the muscles, a mid-frequency band (38.26 and 62.63 Hz) representing more cortical inputs, and a high-frequency band (92.90, 129 and 170.90 Hz) associated with synchronizing motor unit action potentials. Further, the dynamics of changes in intermuscular coupling over time were quantified using the Entropic Half-Life.Main results.Amputees exhibited lower coherency values when vision was removed at 7.56 Hz for the muscle pair of the lower leg. At this frequency, the coherency values of the amputee group also differed from controls for the eyes closed condition. Controls and amputees exhibited opposite coherent behaviors with visual feedback at 7.56 Hz. For the eyes open condition at 129 Hz, the coherency values of amputees and controls differed for the muscle pair of the trunk, and at 170.90 Hz for the muscle pair of the lower leg. Amputees exhibited different dynamics of muscle co-activation at the low frequency band when vision was available.Significance.Altogether, these findings point to the development of neuromuscular adaptations reflected in the strength and dynamics of muscular co-activation.

Design of Experiment Evaluation of a 2.5D Printing Process for Implantable PDMS-based Neural Interfaces.

Current laser fabrication processes for PDMS-based neural interfaces are associated with excessive costs, due to time-consuming manual handling and expensive machinery. The products of this process, specifically embedded metallic electrical tracks, are prone to breakage under mechanical loading, as well as delamination from their surrounding PDMS substrates. In this work, we develop an alternative 2.5D printing process, using electrically conductive PDMS material for the tracks. The entire electrode was fabricated in a custom-made printing setup, which features the possibility of rapid prototyping. The printing performance of the selected materials was evaluated with the aid of statistical methods for experimental design. We found optimal printing parameters for conductive and non-conductive PDMS which allows the fabrication of flexible and stretchable neural interfaces, while simultaneously minimizing the track resistivity.Clinical Relevance- 2.5D printing processes pave the way for individualized neural interfaces to suit the specific needs of every single patient.

Intermuscular coupling and postural control in unilateral transfemoral amputees - a pilot study.

The dynamics of the adjustment of center of pressure (CoP) has been utilized to understand motor control in human pathologies characterized by impairments in postural balance. The control mechanisms that maintain balance can be investigated via the analysis of muscle recruitment using electromyography (EMG) signals. In this work, we combined these two techniques to investigate balance control during upright standing in transfemoral unilateral amputees wearing a prosthesis. The dynamics of the CoP adjustments and EMG-EMG coherence between four muscles of the trunk and lower limb of 5 unilateral transfemoral amputees and 5 age-matched able-bodied participants were quantified during 30 s of quiet standing using the entropic half-life (EnHL) method. Two visual conditions, eyes open and eyes closed, were tested. Overall, the group of amputees presented lower EnHL values (higher dynamics) in their CoP adjustments than controls, especially in their intact limb. The EnHL values of the EMG-EMG coherence time series in the amputee group were lower than the control group for almost all muscle pairs under both visual conditions. Different correlations between the EnHL values of the CoP data and the EMG-EMG coherence data were observed in the amputee and control groups. These preliminary results suggest the onset of distinct neuromuscular adaptations following a unilateral amputation.Clinical Relevance - Understanding neuromuscular adaptation mechanisms after an amputation may serve to design better rehabilitation treatments and novel prosthetic devices with sensory feedback.

Cortical plasticity after hand prostheses use: Is the hypothesis of deafferented cortex "invasion" always true?

OBJECTIVE: To study motor cortex plasticity after a period of training with a new prototype of bidirectional hand prosthesis in three left trans-radial amputees, correlating these changes with the modification of Phantom Limb Pain (PLP) in the same period. METHODS: Each subject underwent a brain motor mapping with Transcranial Magnetic Stimulation (TMS) and PLP evaluation with questionnaires during a six-month training with a prototype of bidirectional hand prosthesis. RESULTS: The baseline motor maps showed in all three amputees a smaller area of muscles representation of the amputated side compared to the intact limb. After training, there was a partial reversal of the baseline asymmetry. The two subjects affected by PLP experienced a statistically significant reduction of pain. CONCLUSIONS: Two apparently opposite findings, the invasion of the "deafferented" cortex by neighbouring areas and the "persistence" of neural structures after amputation, could vary according to different target used for measurement. Our results do not support a correlation between PLP and motor cortical changes. SIGNIFICANCE: The selection of the target and of the task is essential for studies investigating motor brain plasticity. This study boosts against a direct and unique role of motor cortical changes on PLP genesis.

Characterization of multi-channel intraneural stimulation in transradial amputees.

Although peripheral nerve stimulation using intraneural electrodes has been shown to be an effective and reliable solution to restore sensory feedback after hand loss, there have been no reports on the characterization of multi-channel stimulation. A deeper understanding of how the simultaneous stimulation of multiple electrode channels affects the evoked sensations should help in improving the definition of encoding strategies for bidirectional prostheses. We characterized the sensations evoked by simultaneous stimulation of median and ulnar nerves (multi-channel configuration) in four transradial amputees who had been implanted with four TIMEs (Transverse Intrafascicular Multichannel Electrodes). The results were compared with the characterization of single-channel stimulation. The sensations were characterized in terms of location, extent, type, and intensity. Combining two or more single-channel configurations caused a linear combination of the sensation locations and types perceived with such single-channel stimulations. Interestingly, this was also true when two active sites from the same nerve were stimulated. When stimulating in multi-channel configuration, the charge needed from each electrode channel to evoke a sensation was significantly lower than the one needed in single-channel configuration (sensory facilitation). This result was also supported by electroencephalography (EEG) recordings during nerve stimulation. Somatosensory potentials evoked by multi-channel stimulation confirmed that sensations in the amputated hand were perceived by the subjects and that a perceptual sensory facilitation occurred. Our results should help the future development of more efficient bidirectional prostheses by providing guidelines for the development of more complex stimulation approaches to effectively restore multiple sensations at the same time.

Optimal integration of intraneural somatosensory feedback with visual information: a single-case study.

Providing somatosensory feedback to amputees is a long-standing objective in prosthesis research. Recently, implantable neural interfaces have yielded promising results in this direction. There is now considerable evidence that the nervous system integrates redundant signals optimally, weighting each signal according to its reliability. One question of interest is whether artificial sensory feedback is combined with other sensory information in a natural manner. In this single-case study, we show that an amputee with a bidirectional prosthesis integrated artificial somatosensory feedback and blurred visual information in a statistically optimal fashion when estimating the size of a hand-held object. The patient controlled the opening and closing of the prosthetic hand through surface electromyography, and received intraneural stimulation proportional to the object's size in the ulnar nerve when closing the robotic hand on the object. The intraneural stimulation elicited a vibration sensation in the phantom hand that substituted the missing haptic feedback. This result indicates that sensory substitution based on intraneural feedback can be integrated with visual feedback and make way for a promising method to investigate multimodal integration processes.

Long-Term Functionality of Transversal Intraneural Electrodes Is Improved By Dexamethasone Treatment.

Neuroprostheses aimed to restore lost functions after a limb amputation are based on the interaction with the nervous system by means of neural interfaces. Among the different designs, intraneural electrodes implanted in peripheral nerves represent a good strategy to stimulate nerve fibers to send sensory feedback and to record nerve signals to control the prosthetic limb. However, intraneural electrodes, as any device implanted in the body, induce a foreign body reaction (FBR) that results in the tissue encapsulation of the device. The FBR causes a progressive decline of the electrode functionality over time due to the physical separation between the electrode active sites and the axons to interface. Modulation of the inflammatory response has arisen as a good strategy to reduce the FBR and maintain electrode functionality. In this study transversal intraneural multi-channel electrodes (TIMEs) were implanted in the rat sciatic nerve and tested for 3 months to evaluate stimulation and recording capabilities under chronic administration of dexamethasone. Dexamethasone treatment significantly reduced the threshold for evoking muscle responses during the follow-up compared to saline-treated animals, without affecting the selectivity of stimulation. However, dexamethasone treatment did not improve the signal-to-noise ratio of the recorded neural signals. Dexamethasone treatment allowed to maintain more working active sites along time than saline treatment. Thus, systemic administration of dexamethasone appears as a useful treatment in chronically implanted animals with neural electrodes as it increases the number of functioning contacts of the implanted TIME and reduces the intensity needed to stimulate the nerve.

Electrochemical Stability of Thin-Film Platinum as Suitable Material for Neural Stimulation Electrodes.

Only thin-film technology can satisfy the requirements of high spatial selectivity at high-channel-count electrode array designs by simultaneously good conformability to the targeted tissue through mechanical flexibility enriching future applications of functional neural stimulation. However, caused by the high impact of the microstructure on the mechanical and electrochemical film properties, varying fabrication processes of the same thin-film makes the difference between acute and chronic long-term stable electrodes. The influence of standard clinical electrical pulsing on flexible polyimide-based thin-film platinum electrodes for neuroprostheses, either sputter deposited or evaporated, and different diameters was assessed and compared. The electrochemical and morphological analysis showed a higher corrosion susceptibility and electrochemical degradation for the sputter deposited platinum electrodes with even total failures of smaller diameters. In contrast, the evaporated thin-films provided itself as more stable and reliable metallization with also smaller electrodes keeping their film integrity intact over the experimental period, -appearing to be the preferable material for improving thin-film electrodes' longevity.

Electrochemical Characterization and Surface Analysis of Activated Glassy Carbon Neural Electrodes.

Glassy carbon (GC) neural electrodes have recently gained visibility thanks to their great resistance to corrosion combined to their ability to record and stimulate neuronal activity. To enhance their electrochemical performance, GC electrodes are often subjected to activation, either through electrical or chemical means. In this study, we have compared the activation of GC electrodes performed using electrical biphasic pulses to chemically-induced activation. Because the GC electrodes used for this research are made by pyrolysing SU-8 photoresist - and thus they undergo massive shrinkage during carbonization - 2 electrode diameters were investigated (300 and 50 µm) with the aim of understanding if their surface composition and their ability to get activated change with their geometry. Chemical activation was induced by immersing the electrodes in 2 solutions: A1 and A2, 30 and 150 mM H2O2/PBS (hydrogen peroxide in phosphate buffered saline) respectively. The comparison between activation methods was done by measuring GC electrodes impedance, charge storage capacity (CSC) and by performing surface analysis, before and after the treatments. Results show that impedance drops in all the cases, especially at low frequencies (<; 1 kHz) and that there is always an increase in CSC. Raman spectra and relative intensities of disorder are very similar for both electrode diameters and before and after every treatment. X-Ray photoelectron spectroscopy (XPS) interestingly shows graphite content only on the 300 µm electrodes and a high percentage of graphite only on the pristine one. Apart from oxygen and nitrogen, no other species were present on the electrodes surface. In conclusion, both electrically and chemically-induced activation help improving the electrochemical performance of GC electrodes without harming them.

Comparison of linear frequency and amplitude modulation for intraneural sensory feedback in bidirectional hand prostheses.

Recent studies have shown that direct nerve stimulation can be used to provide sensory feedback to hand amputees. The intensity of the elicited sensations can be modulated using the amplitude or frequency of the injected stimuli. However, a comprehensive comparison of the effects of these two encoding strategies on the amputees' ability to control a prosthesis has not been performed. In this paper, we assessed the performance of two trans-radial amputees controlling a myoelectric hand prosthesis while receiving grip force sensory feedback encoded using either linear modulation of amplitude (LAM) or linear modulation of frequency (LFM) of direct nerve stimulation (namely, bidirectional prostheses). Both subjects achieved similar and significantly above-chance performance when they were asked to exploit LAM or LFM in different tasks. The feedbacks allowed them to discriminate, during manipulation through the robotic hand, objects of different compliances and shapes or different placements on the prosthesis. Similar high performances were obtained when they were asked to apply different levels of force in a random order on a dynamometer using LAM or LFM. In contrast, only the LAM strategy allowed the subjects to continuously modulate the grip pressure on the dynamometer. Furthermore, when long-lasting trains of stimulation were delivered, LFM strategy generated a very fast adaptation phenomenon in the subjects, which caused them to stop perceiving the restored sensations. Both encoding approaches were perceived as very different from the touch feelings of the healthy limb (natural). These results suggest that the choice of specific sensory feedback encodings can have an effect on user performance while grasping. In addition, our results invite the development of new approaches to provide more natural sensory feelings to the users, which could be addressed by a more biomimetic strategy in the future.

Low temperature approach for high density electrical feedthroughs for neural implants using maskless fabrication techniques.

Implantable electronic packages for neural implants utilize reliable electrical feedthroughs that connect the inside of a sealed capsule to the components that are exposed to the surrounding body tissue. With the ongoing miniaturization of implants requiring ever higher integration densities of such feedthroughs new technologies have to be investigated. The presented work investigates the sealing of vertical feedthroughs in aluminum-oxide-substrates with gold stud-bumps. The technology enables integration densities of up to 1600/cm 2 while delivering suitable water leak rates for realistic implantation durations of miniaturized packages (feedthrough-count $>50$, package-volume $<2$ cm $^{3})$ of more than 50 years. All manufacturing steps require temperatures below $420 ^{\circ}\mathrm {C}$ and are suitable for maskless rapid prototyping.

Neurophysiological Evaluation of a Customizable µECoG-based Wireless Brain Implant.

The number of implantable bidirectional neural interfaces available for neuroscientific research applications is still limited, despite the rapidly increasing number of customized components. We previously reported on how to translate available components into "ready-to-use" wireless implantable systems utilizing components off-the-shelf (COTS). The aim of the present study was to verify the viability of a micro-electrocorticographic ($\mu $ECoG) device built by this approach. Functionality for both neural recording and stimulation was evaluated in an ovine animal model using acoustic stimuli and cortical electrical stimulation, respectively. We show that auditory evoked responses were reliably recorded in both time and frequency domain and present data that demonstrates the cortical electrical stimulation functionality. The successful recording of neuronal activity suggests that the device can compete with existing implantable systems as a neurotechnological research tool.

Micro-folded 3D neural electrodes fully integrated in polyimide.

Recent neural interfaces are characterized by high functionality and good adaptation to the target tissue. Still, the underlying manufacturing process is mainly planar and so are the device and contact surface. Therefore, three-dimensional structures to contact neuronal tissue are desired to gain higher selectivity. In the present study, local bending structures integrated in flexible electrode arrays based on polyimide are investigated. The bending is achieved by the contraction of a second polyimide (Durimide) that is embedded into grooves with a width of a few micrometers. The angle of the bending can be controlled with a high accuracy from 3 to 20 degrees by changing the geometry of the grooves and the imidization temperature These bending structures can be combined to achieve any desired angle for specific applications.

In Situ Measurement of Stimulus Induced pH Changes Using ThinFilm Embedded IrOx pH Electrodes.

The high complexity of the biological response to implanted materials builds a serious barrier against implanted recording and stimulation electrode arrays to succeed in clinically relevant chronic studies. Some of the cell and molecular interactions and their contribution to inflammation and device failure are still unclear. The interrelated mechanisms leading to tissue damage and electrode array failure during simultaneous faradaic, electrochemical reactions and biological response under electrical stimulation are not understood sufficiently. One variable, with which inflammatory and electrode surface processes can be analyzed and assessed, is the pH change in the immediate environment of the material-tissue interface. Here, the greatest challenges are in the biocompatibility and in-vivo long-term stability of selected sensor materials, the measurement of small transient pH oscillations and positioning of the sensor at a defined and nearest possible distance in the micrometer range, to the site of activity without the pH sensing being affected by the material- issue interactions itself. This work represents the in-situ measurement of local and transient pH changes at apulsed electrode with an embedded in-vivo compatible pH sensor and therein differentiating from current approaches of pH sensing during electrical stimulation.

Integrated optoelectronic microprobes.

Optogenetics opened not only new exciting opportunities to interrogate the nervous system but also requires adequate probes to facilitate these wishes. Therefore, a multidisciplinary effort is essential to match these technical opportunities with biological needs in order to establish a stable and functional material-tissue interface. This in turn can address an optical intervention of the genetically modified, light sensitive cells in the nervous system and recording of electrical signals from single cells and neuronal networks that result in behavioral changes. In this review, we present the state of the art of optoelectronic probes and assess advantages and challenges of the different design approaches. At first, we discuss mechanisms and processes at the material-tissue interface that influence the performance of optoelectronic probes in acute and chronic implantations. We classify optoelectronic probes by their property of delivering light to the tissue: by waveguides or by integrated light sources at the sites of intervention. Both approaches are discussed with respect to size, spatial resolution, opportunity to integrate electrodes for electrical recording and potential interactions with the target tissue. At last, we assess translational aspects of the state of the art. Long-term stability of probes and the opportunity to integrate them into fully implantable, wireless systems are a prerequisite for chronic applications and a transfer from fundamental neuroscientific studies into treatment options for diseases and clinical trials.

Precise localization of silicone-based intercranial planar electrodes in magnetic resonance imaging.

Intercranial planar electrodes enable neural recordings with high spatial resolution in diagnosis as well as for treatments. The value of the measurements increases with the precision of localization of the electrodes related to the individual anatomy. In this context, post-implantation MRI provides excellent soft tissue contrast, but the accurate localization of electrodes is impaired by magnetic susceptibility artifacts. We have addressed this problem without adding a substantial burden to the electrode fabrication process. Simple silicone reference structures were strategically placed on the implant surface to visualize the electrodes position in MRI. These reference structures allowed high precision electrode localization independently of electrode imaging artifacts. This implant manufacturing approach could prove extremely useful in combination with existing image processing pipelines.

Nanostructured platinum as an electrochemically and mechanically stable electrode coating.

Nanostructured materials exhibit large electrochemical surface areas and are thus of high interest for neural interfaces where low impedance and high charge transfer characteristics are desired. While progress in nanotechnology successively enabled smaller feature sizes and thus improved electrochemical properties, concerns were raised with respect to the mechanical stability of such nano structures for use in neural applications. In our study we address these concerns by investigating the mechanical and electrochemical stability of nanostructured platinum. Neural probes with nano-Pt were exposed to exaggerated stress tests resembling insertion into neural tissue over 60 mm distance or long-term stimulation over 240 M biphasic current pulses. Thereby only insignificant changes in electrochemical properties and morphological appearance could be observed in response to the test, proving that nanostructured platinum exhibits outstanding stability. With this finding, a major concern in using nanostructured materials for interfacing neural tissue could be eliminated, demonstrating the high potential of nanostructured platinum for neuroprosthetic devices.