A Wearable Real-Time System for Simultaneous Wireless Power and Data Transmission to Cortical Visual Prosthesis.

Wireless, miniaturised and distributed neural interfaces are emerging neurotechnologies. Although extensive research efforts contribute to their technological advancement, the need for real-time systems enabling simultaneous wireless information and power transfer toward distributed neural implants remains crucial. Here we present a complete wearable system including a software for real-time image capturing, processing and digital data transfer; an hardware for high radiofrequency generation and modulation via amplitude shift keying; and a 3-coil inductive link adapt to operate with multiple miniaturised receivers. The system operates in real-time with a maximum frame rate of 20 Hz, reconstructing each frame with a matrix of 32 × 32 pixels. The device generates a carrier frequency of 433.92 MHz. It transmits the highest power of 32 dBm with a data rate of 6 Mbps and a variable modulation index as low as 8 %, thus potentially enabling wireless communication with 1024 miniaturised and distributed intracortical microstimulators. The system is primarily conceived as an external wearable device for distributed cortical visual prosthesis covering a visual field of 20 °. At the same time, it is modular and versatile, being suitable for multiple applications requiring simultaneous wireless information and power transfer to large-scale neural interfaces.

A Frequency-Switching Inductive Power Transfer System for Wireless, Miniaturised and Large-Scale Neural Interfaces.

Three-coil inductive power transfer is the state-of-the-art solution to power multiple miniaturised neural implants. However, the maximum delivered power is limited by the efficiency of the powering link and safety constrains. Here we propose a frequency-switching inductive link, where the passive resonator normally used in a three-coil link is replaced by an active resonator. It receives power from the external transmitter via a two-coil inductive link at the low frequency of 13.56 MHz. Then, it switches the operating frequency to the higher frequency of 433.92 MHz through a dedicated circuitry. Last, it transmits power to 1024 miniaturised implants via a three-coil inductive link using an array of 37 focusing resonators for a brain coverage of 163.84 mm 2. Our simulations reported a power transfer efficiency of 0.013% and a maximum power delivered to the load of 1970 µ W under safety-constrains, which are respectively two orders of magnitude and more than six decades higher compared to an equivalent passive three-coil link. The frequency-switching inductive system is a scalable and highly versatile solution for wireless, miniaturised and large-scale neural interfaces.

An actor-model framework for visual sensory encoding.

A fundamental challenge in neuroengineering is determining a proper artificial input to a sensory system that yields the desired perception. In neuroprosthetics, this process is known as artificial sensory encoding, and it holds a crucial role in prosthetic devices restoring sensory perception in individuals with disabilities. For example, in visual prostheses, one key aspect of artificial image encoding is to downsample images captured by a camera to a size matching the number of inputs and resolution of the prosthesis. Here, we show that downsampling an image using the inherent computation of the retinal network yields better performance compared to learning-free downsampling methods. We have validated a learning-based approach (actor-model framework) that exploits the signal transformation from photoreceptors to retinal ganglion cells measured in explanted mouse retinas. The actor-model framework generates downsampled images eliciting a neuronal response in-silico and ex-vivo with higher neuronal reliability than the one produced by a learning-free approach. During the learning process, the actor network learns to optimize contrast and the kernel's weights. This methodological approach might guide future artificial image encoding strategies for visual prostheses. Ultimately, this framework could be applicable for encoding strategies in other sensory prostheses such as cochlear or limb.

Changes Over Time in the Electrode/Brain Interface Impedance: An Ex-Vivo Study.

Closed-loop neural implants based on continuous brain activity recording and intracortical microstimulation are extremely effective and promising devices to monitor and address many neurodegenerative diseases. The efficiency of these devices depends on the robustness of the designed circuits which rely on precise electrical equivalent models of the electrode/brain interface. This is true in the case of amplifiers for differential recording, voltage or current drivers for neurostimulation, and potentiostats for electrochemical bio-sensing. This is of paramount importance, especially for the next generation of wireless and ultra-miniaturised CMOS neural implants. Circuits are usually designed and optimized considering the electrode/brain impedance with a simple electrical equivalent model whose parameters are stationary over time. However, the electrode/brain interfacial impedance varies simultaneously in frequency and in time after implantation. The aim of this study is to monitor the impedance changes occurring on microelectrodes inserted in ex-vivo porcine brains to derive an opportune electrode/brain model describing the system and its evolution in time. In particular, impedance spectroscopy measurements have been performed for 144 hours to characterise the evolution of the electrochemical behaviour in two different setups analysing both the neural recording and the chronic stimulation scenarios. Then, different equivalent electrical circuit models have been proposed to describe the system. Results showed a decrease in the resistance to charge transfer, attributed to the interaction between biological material and the electrode surface. These findings are crucial to support circuit designers in the field of neural implants.

The role of the visual field size in artificial vision.

Objective. Artificial vision has been and still is the subject of intense research. The ultimate goal is to help blind people in their daily life. Approaches to artificial vision, including visual prostheses and optogenetics, have strongly focused on restoring high visual acuity for object recognition and reading. Consequently, clinical trials were primarily focused on these parameters.Approach. Alternatively, enlarging the visual field (VF) size could significantly improve artificial vision.Main results. I propose that approaches towards artificial vision address the challenge of creating this rudimental form of sight within a large VF.Significance. Enlarging the VF size will enable users to improve their mobility and perform visually-driven search tasks. Eventually, it could make artificial vision more efficient, comfortable and acceptable from the user's point of view.

Conformable neural interface based on off-stoichiometry thiol-ene-epoxy thermosets.

Off-stoichiometry thiol-ene-epoxy (OSTE+) thermosets show low permeability to gases and little absorption of dissolved molecules, allow direct low-temperature dry bonding without surface treatments, have a low Young's modulus, and can be manufactured via UV polymerisation. For these reasons, OSTE+ thermosets have recently gained attention for the rapid prototyping of microfluidic chips. Moreover, their compatibility with standard clean-room processes and outstanding mechanical properties make OSTE+ an excellent candidate as a novel material for neural implants. Here we exploit OSTE+ to manufacture a conformable multilayer micro-electrocorticography array with 16 platinum electrodes coated with platinum black. The mechanical properties allow conformability to curved surfaces such as the brain. The low permeability and strong adhesion between layers improve the stability of the device. Acute experiments in mice show the multimodal capacity of the array to record and stimulate the neural tissue by smoothly conforming to the mouse cortex. Devices are not cytotoxic, and immunohistochemistry stainings reveal only modest foreign body reaction after two and six weeks of chronic implantation. This work introduces OSTE+ as a promising material for implantable neural interfaces.

POLYRETINA restores light responses in vivo in blind Göttingen minipigs.

Retinal prostheses hold the potential for artificial vision in blind people affected by incurable diseases of the outer retinal layer. Available technologies provide only a small field of view: a significant limitation for totally blind people. To overcome this problem, we recently proposed a large and high-density photovoltaic epiretinal device, known as POLYRETINA. Here, we report the in vivo assessment of POLYRETINA. First, we characterise a model of chemically-induced blindness in Göttingen minipigs. Then, we develop and test a minimally invasive injection procedure to insert the large epiretinal implant into the eye. Last, we show that POLYRETINA restores light-evoked cortical responses in blind animals at safe irradiance levels. These results indicate that POLYRETINA holds the potential for artificial vision in totally blind patients affected by retinitis pigmentosa.

Three-dimensional multilayer concentric bipolar electrodes restrict spatial activation in optic nerve stimulation.

Objective.Intraneural nerve interfaces often operate in a monopolar configuration with a common and distant ground electrode. This configuration leads to a wide spreading of the electric field. Therefore, this approach is suboptimal for intraneural nerve interfaces when selective stimulation is required.Approach.We designed a multilayer electrode array embedding three-dimensional concentric bipolar (CB) electrodes. First, we validated the higher stimulation selectivity of this new electrode array compared to classical monopolar stimulation using simulations. Next, we compared themin-vivoby intraneural stimulation of the rabbit optic nerve and recording evoked potentials in the primary visual cortex.Main results.Simulations showed that three-dimensional CB electrodes provide a high localisation of the electric field in the tissue so that electrodes are electrically independent even for high electrode density. Experimentsin-vivohighlighted that this configuration restricts spatial activation in the visual cortex due to the fewer fibres activated by the electric stimulus in the nerve.Significance.Highly focused electric stimulation is crucial to achieving high selectivity in fibre activation. The multilayer array embedding three-dimensional CB electrodes improves selectivity in optic nerve stimulation. This approach is suitable for other neural applications, including bioelectronic medicine.

Virtual reality validation of naturalistic modulation strategies to counteract fading in retinal stimulation.

Objective. Temporal resolution is a key challenge in artificial vision. Several prosthetic approaches are limited by the perceptual fading of evoked phosphenes upon repeated stimulation from the same electrode. Therefore, implanted patients are forced to perform active scanning, via head movements, to refresh the visual field viewed by the camera. However, active scanning is a draining task, and it is crucial to find compensatory strategies to reduce it.Approach. To address this question, we implemented perceptual fading in simulated prosthetic vision using virtual reality. Then, we quantified the effect of fading on two indicators: the time to complete a reading task and the head rotation during the task. We also tested if stimulation strategies previously proposed to increase the persistence of responses in retinal ganglion cells to electrical stimulation could improve these indicators.Main results. This study shows that stimulation strategies based on interrupted pulse trains and randomisation of the pulse duration allows significant reduction of both the time to complete the task and the head rotation during the task.Significance. The stimulation strategy used in retinal implants is crucial to counteract perceptual fading and to reduce active head scanning during prosthetic vision. In turn, less active scanning might improve the patient's comfort in artificial vision.

Transient electronics: new opportunities for implantable neurotechnology.

Neurotechnology includes artificial devices integrated with the neural tissue to mitigate the burden of neurological and mental disorders. This field has significantly expanded its range of applications thanks to the development of flexible, stretchable and injectable electronics. Now, the emergence of green electronics adds a new asset to the neurotechnology toolbox. Transient neurotechnology reduces the side effects of chronic implants and transforms inert devices into bio-active and bio-responsive structures. Ultimately, it holds the potential of bridging together technological devices with modern approaches in regenerative medicine. This review focuses on the rising potential of transient neurotechnology for human benefit, comprehensively summarises recent achievements and highlights feature needs and challenges.

All-polymeric transient neural probe for prolonged in-vivo electrophysiological recordings.

Transient bioelectronics has grown fast, opening possibilities never thought before. In medicine, transient implantable devices are interesting because they could eliminate the risks related to surgical retrieval and reduce the chronic foreign body reaction. Despite recent progress in this area, the potential of transient bioelectronics is still limited by their short functional lifetime owed to the fast dissolution rate of degradable metals, which is typically a few days or weeks. Here we report that a switch from degradable metals to an entirely polymer-based approach allows for a slower degradation process and a longer lifetime of the transient probe, thus opening new possibilities for transient medical devices. As a proof-of-concept, we fabricated all-polymeric transient neural probes that can monitor brain activity in mice for a few months, rather than a few days or weeks. Also, we extensively evaluated the foreign body reaction around the implant during the probe degradation. This kind of devices might pave the way for several applications in neuroprosthetics.

A machine-learning algorithm correctly classifies cortical evoked potentials from both visual stimulation and electrical stimulation of the optic nerve.

Objective. Optic nerve's intraneural stimulation is an emerging neuroprosthetic approach to provide artificial vision to totally blind patients. An open question is the possibility to evoke individual non-overlapping phosphenes via selective intraneural optic nerve stimulation. To begin answering this question, first, we aim at showing in preclinical experiments with animals that each intraneural electrode could evoke a distinguishable activity pattern in the primary visual cortex.Approach. We performed both patterned visual stimulation and patterned electrical stimulation in healthy rabbits while recording evoked cortical activity with an electrocorticogram array in the primary visual cortex. Electrical stimulation was delivered to the optic nerve with the intraneural array OpticSELINE. We used a support vector machine algorithm paired to a linear regression model to classify cortical responses originating from visual stimuli located in different portions of the visual field and electrical stimuli from the different electrodes of the OpticSELINE.Main results. Cortical activity induced by visual and electrical stimulation could be classified with nearly 100% accuracy relative to the specific location in the visual field or electrode in the array from which it originated. For visual stimulation, the accuracy increased with the separation of the stimuli and reached 100% for separation higher than 7°. For electrical stimulation, at low current amplitudes, the accuracy increased with the distance between electrodes, while at higher current amplitudes, the accuracy was nearly 100% already for the shortest separation.Significance. Optic nerve's intraneural stimulation with the OpticSELINE induced discernible cortical activity patterns. These results represent a necessary condition for an optic nerve prosthesis to deliver vision with non-overlapping phosphene. However, clinical investigations will be required to assess the translation of these results into perceptual phenomena.

Naturalistic spatiotemporal modulation of epiretinal stimulation increases the response persistence of retinal ganglion cell.

Objective.Retinal stimulation in blind patients evokes the sensation of discrete points of light called phosphenes, which allows them to perform visually guided tasks, such as orientation, navigation, object recognition, object manipulation and reading. However, the clinical benefit of artificial vision in profoundly blind patients is still tenuous, as several engineering and biophysical obstacles keep it far away from natural perception. The relative preservation of the inner retinal neurons in hereditary degenerative retinal diseases, such as retinitis pigmentosa, supports artificial vision through the network-mediated stimulation of retinal ganglion cells (RGCs). However, the response of RGCs to repeated electrical stimulation rapidly declines, primarily because of the intrinsic desensitisation of their excitatory network. In patients, upon repetitive stimulation, phosphenes fade out in less than half of a second, which drastically limits the understanding of the percept.Approach.A more naturalistic stimulation strategy, based on spatiotemporal modulation of electric pulses, could overcome the desensitisation of RGCs. To investigate this hypothesis, we performed network-mediated epiretinal stimulations paired to electrophysiological recordings in retinas explanted from both male and female retinal degeneration 10 mice.Main results.The results showed that the spatial and temporal modulation of the network-mediated epiretinal stimulation prolonged the persistence of the RGC's response from 400 ms up to 4.2 s.Significance.A time-varied, non-stationary and interrupted stimulation of the retinal network, mimicking involuntary microsaccades, might reduce the fading of the visual percept and improve the clinical efficacy of retinal implants.

Flow driven robotic navigation of microengineered endovascular probes.

Minimally invasive medical procedures, such as endovascular catheterization, have considerably reduced procedure time and associated complications. However, many regions inside the body, such as in the brain vasculature, still remain inaccessible due to the lack of appropriate guidance technologies. Here, experimentally and through numerical simulations, we show that tethered ultra-flexible endovascular microscopic probes can be transported through tortuous vascular networks with minimal external intervention by harnessing hydrokinetic energy. Dynamic steering at bifurcations is performed by deformation of the probe head using magnetic actuation. We developed an endovascular microrobotic toolkit with a cross-sectional area that is orders of magnitude smaller than the smallest catheter currently available. Our technology has the potential to improve state-of-the-art practices as it enhances the reachability, reduces the risk of iatrogenic damage, significantly increases the speed of robot-assisted interventions, and enables the deployment of multiple leads simultaneously through a standard needle injection and saline perfusion.

Miniaturised Wireless Power Transfer Systems for Neurostimulation: A Review.

In neurostimulation, wireless power transfer is an efficient technology to overcome several limitations affecting medical devices currently used in clinical practice. Several methods were developed over the years for wireless power transfer. In this review article, we report and discuss the three most relevant methodologies for extremely miniaturised implantable neurostimulators: ultrasound coupling, inductive coupling and capacitive coupling. For each powering method, the discussion starts describing the physical working principle. In particular, we focus on the challenges given by the miniaturisation of the implanted integrated circuits and the related ad-hoc solutions for wireless power transfer. Then, we present recent developments and progresses in wireless power transfer for biomedical applications. Last, we compare each technique based on key performance indicators to highlight the most relevant and innovative solutions suitable for neurostimulation, with the gaze turned towards miniaturisation.

Virtual reality simulation of epiretinal stimulation highlights the relevance of the visual angle in prosthetic vision.

OBJECTIVE: Retinal prostheses hold the potential for artificial vision in blind patients suffering from outer retinal dystrophies. The optimal number, density and coverage of the electrodes that a retinal prosthesis should have to provide adequate artificial vision in daily activities is still an open question and an important design parameter needed to develop better implants. APPROACH: To address this question, we investigated the interaction between the visual angle, the pixel number and the pixel density without being limited by a small electrode count. We implemented prosthetic vision in a virtual reality environment in order to simulate the real-life experience of using a retinal prosthesis. We designed four different tasks simulating: object recognition, word reading, perception of a descending step and crossing a street. MAIN RESULTS: The results of our study showed that in all the tasks the visual angle played the most significant role in improving the performance of the participant. SIGNIFICANCE: The design of new retinal prostheses should take into account the relevance of the restored visual angle to provide a helpful and valuable visual aid to profoundly or totally blind patients.