A Wireless Neural Stimulator IC for Cortical Visual Prosthesis.

We propose a 0.25 × 0.25 × 0.3 mm (~0.02 mm3) optically powered mote for visual cortex stimulation to restore vision. Up to 1024 implanted motes can be individually addressed. The complete StiMote system was confirmed fully functional when optically powered and cortex stimulation was confirmed in-vivo with a live rat brain.

Full-field, conformal epiretinal electrode array using hydrogel and polymer hybrid technology.

Shape-morphable electrode arrays can form 3D surfaces to conform to complex neural anatomy and provide consistent positioning needed for next-generation neural interfaces. Retinal prostheses need a curved interface to match the spherical eye and a coverage of several cm to restore peripheral vision. We fabricated a full-field array that can (1) cover a visual field of 57° based on electrode position and of 113° based on the substrate size; (2) fold to form a compact shape for implantation; (3) self-deploy into a curvature fitting the eye after implantation. The full-field array consists of multiple polymer layers, specifically, a sandwich structure of elastomer/polyimide-based-electrode/elastomer, coated on one side with hydrogel. Electrodeposition of high-surface-area platinum/iridium alloy significantly improved the electrical properties of the electrodes. Hydrogel over-coating reduced electrode performance, but the electrodes retained better properties than those without platinum/iridium. The full-field array was rolled into a compact shape and, once implanted into ex vivo pig eyes, restored to a 3D curved surface. The full-field retinal array provides significant coverage of the retina while allowing surgical implantation through an incision 33% of the final device diameter. The shape-changing material platform can be used with other neural interfaces that require conformability to complex neuroanatomy.

Spatial Transcriptomics as a Novel Approach to Redefine Electrical Stimulation Safety.

Current standards for safe delivery of electrical stimulation to the central nervous system are based on foundational studies which examined post-mortem tissue for histological signs of damage. This set of observations and the subsequently proposed limits to safe stimulation, termed the "Shannon limits," allow for a simple calculation (using charge per phase and charge density) to determine the intensity of electrical stimulation that can be delivered safely to brain tissue. In the three decades since the Shannon limits were reported, advances in molecular biology have allowed for more nuanced and detailed approaches to be used to expand current understanding of the physiological effects of stimulation. Here, we demonstrate the use of spatial transcriptomics (ST) in an exploratory investigation to assess the biological response to electrical stimulation in the brain. Electrical stimulation was delivered to the rat visual cortex with either acute or chronic electrode implantation procedures. To explore the influence of device type and stimulation parameters, we used carbon fiber ultramicroelectrode arrays (7 µm diameter) and microwire electrode arrays (50 µm diameter) delivering charge and charge density levels selected above and below reported tissue damage thresholds (range: 2-20 nC, 0.1-1 mC/cm2). Spatial transcriptomics was performed using Visium Spatial Gene Expression Slides (10x Genomics, Pleasanton, CA, United States), which enabled simultaneous immunohistochemistry and ST to directly compare traditional histological metrics to transcriptional profiles within each tissue sample. Our data give a first look at unique spatial patterns of gene expression that are related to cellular processes including inflammation, cell cycle progression, and neuronal plasticity. At the acute timepoint, an increase in inflammatory and plasticity related genes was observed surrounding a stimulating electrode compared to a craniotomy control. At the chronic timepoint, an increase in inflammatory and cell cycle progression related genes was observed both in the stimulating vs. non-stimulating microwire electrode comparison and in the stimulating microwire vs. carbon fiber comparison. Using the spatial aspect of this method as well as the within-sample link to traditional metrics of tissue damage, we demonstrate how these data may be analyzed and used to generate new hypotheses and inform safety standards for stimulation in cortex.

Progressive Retinal Degeneration Increases Cortical Response Latency of Light Stimulation but Not of Electric Stimulation.

Purpose: The brain is known to change functionally and structurally in response to blindness, but less is known about the effects of restoration of cortical input on brain function. Here, we present a preliminary study to observe alterations in visual and electrical evoked cortical potentials as a function of age in a clinically relevant animal model of retinitis pigmentosa. Methods: We recorded brain potentials elicited by light (visual evoked potentials [VEPs]) or corneal electrical stimulation (electrical evoked response [EER]) in retinal degenerate animal model LE-P23H-1. We used a linear mixed model to examine the effects of age on latency and amplitude of VEP and EER age groups P120, P180, and P360. Results: VEP N1, P1, and N2 latency and amplitude were analyzed across animal age. For 1 Hz VEP, N1 latency increased significantly with animal age (slope = 0.053 ± 0.020 ms/day, P < 0.01). For 10 Hz VEP, N1, P1, and N2 latency increased significantly with animal age (slope = 0.104 ± 0.011, 0.135 ± 0.011, 0.087 ± 0.023 ms/day, and P < 0.001 for all VEP peaks). Conversely, EER latency did not change with age. Signal amplitude of VEP or EER did not change with age. Conclusions: Cortical potentials evoked by electrical stimulation of the retina do not diminish in spite of continued retinal degeneration in P23H rats. Translational Relevance: These findings suggest that retinal bioelectronic treatments of retinitis pigmentosa will activate cortex consistently despite variations in outer retinal degeneration. Clinical studies of retinal stimulation should consider varying retinitis pigmentosa genotypes as part of the experimental design.

Experimental factors effecting stability of Electrochemical Impedance Spectroscopy Measurements.

Impedance measurement using Electrochemical Impedance Spectroscopy is a widely utilized technique in neural electrodes. Research and clinical devices that incorporate stimulating and recording microelectrodes routinely characterize the material's integrity and its functionality through impedance measurement. Nominal impedance values ensure a stable neural electrode-tissue contact capable of passing through power efficient electric signals with desired signal-tonoise ratio or effective volume coverage. However, the complexity of the in vivo environment limits the usage of the three-electrode setup, which has been accepted as the ideal method in providing a stable impedance measurement. Impedance data measured from microelectrodes in threeelectrode and two-electrode setups show that the two setups have similar outcomes in terms of the impedance modulus over a 0.5 Hz-100 kHz frequency range. Usage of a platinum counter electrode lowered the overall variance in impedance readings compared to the stainless steel counter electrode. However, correlation coefficient values $(>0.97)$ between three-electrode and two-electrode setups show that impedance values seldom deviate due to changes in electrode setup. Based on the results of this study, the usage of the two-electrode setup in vivo allowed acceptable electrochemical impedance spectroscopy accuracy, and the utilization of a platinum counter electrode is recommended to reduce measurement variance.

Assessment of Ventriculoperitoneal Shunt Function Using Ultrasound Characterization of Valve Interface Oscillation as a Proxy.

Objective Ventricular shunts are a mainstay of hydrocephalus treatment, but the detection of its clinical failure often relies on circumstantial evidence. A direct, non-interventional method for reliably evaluating cerebrospinal fluid (CSF) function does not exist due to the difficulty of measuring in vivo flow characteristics. The objective of this study is to apply a novel method of ultrasound monitoring to characterize the oscillation observed during pulsatile CSF flow and failure states in an in vitro and cadaveric model.   Method In this proof-of-concept report, ultrasound is utilized to noninvasively monitor the shunt valve and characterize its mechanical response to different flow conditions. In vitro and in situ testing was carried out by running deionized water through a ventriculoperitoneal shunt (VPS) system using a pulsatile flow generator to replicate the flow rates expected in vivo. Different flow conditions were then tested: no flow, normal flow, proximal obstruction, and distal obstruction. Ultrasound data taken from the pressure relief valve were analyzed to determine differences in the displacement of valve components over time between flow states. Results Displacement patterns of the four different flow conditions were determined by directly tracking the changes from the M-mode plots. Each pattern was found to be distinct and repeatable with statistically significant results found when comparing the normal flow condition to distal and proximal obstruction cases. Conclusions Each of the flow conditions was found to have a distinct displacement profile, demonstrating that ultrasound imaging of the shunt valve can be used to accurately differentiate between flow and failure conditions. Ultrasound monitoring may be a promising adjunct approach in determining the need for surgical shunt exploration.

In vivo Characterization of Amorphous Silicon Carbide As a Biomaterial for Chronic Neural Interfaces.

Implantable microelectrode arrays (MEAs) offer clinical promise for prosthetic devices by enabling restoration of communication and control of artificial limbs. While proof-of-concept recordings from MEAs have been promising, work in animal models demonstrates that the obtained signals degrade over time. Both material robustness and tissue response are acknowledged to have a role in device lifetime. Amorphous Silicon carbide (a-SiC), a robust material that is corrosion resistant, has emerged as an alternative encapsulation layer for implantable devices. We systematically examined the impact of a-SiC coating on Si probes by immunohistochemical characterization of key markers implicated in tissue-device response. After implantation, we performed device capture immunohistochemical labeling of neurons, astrocytes, and activated microglia/macrophages after 4 and 8 weeks of implantation. Neuron loss and microglia activation were similar between Si and a-SiC coated probes, while tissue implanted with a-SiC displayed a reduction in astrocytes adjacent to the probe. These results suggest that a-SiC has a similar biocompatibility profile as Si, and may be suitable for implantable MEA applications as a hermetic coating to prevent material degradation.