In-vivo testing of a novel wireless intraspinal microstimulation interface for restoration of motor function following spinal cord injury.

BACKGROUND: Spinal cord injury causes a drastic loss in motor and sensory function. Intraspinal microstimulation (ISMS) is an electrical stimulation method developed for restoring motor function by activating the spinal networks below the level of injury. Current ISMS technology uses fine penetrating microwires to stimulate the ventral horn of the lumbar enlargement. The penetrating wires traverse the dura mater through a transdural conduit that connects to an implantable pulse generator. OBJECTIVE: A wireless, fully intradural ISMS implant was developed to mitigate the potential complications associated with the transdural conduit, including tethering and leakage of cerebrospinal fluid. METHODS: Two wireless floating microelectrode array (WFMA) devices were implanted in the lumbar enlargement of an adult domestic pig. Voltage transients were used to assess the electrochemical stability of the interface. Manual flexion and extension movements of the spine were performed to evaluate the mechanical stability of the interface. Post-mortem 9T MRI imaging was used to confirm the location of the electrodes. RESULTS: The WFMA-based ISMS interface successfully evoked extension and flexion movements of the hip joint. Stimulation thresholds remained stable following manual extension and flexion of the spine. CONCLUSION: The preliminary results demonstrate the surgical feasibility as well as the functionality of the proposed wireless ISMS system.

Chronic stability of activated iridium oxide film voltage transients from wireless floating microelectrode arrays.

Successful monitoring of the condition of stimulation electrodes is critical for maintaining chronic device performance for neural stimulation. As part of pre-clinical safety testing in preparation for a visual prostheses clinical trial, we evaluated the stability of the implantable devices and stimulation electrodes using a combination of current pulsing in saline and in canine visual cortex. Specifically, in saline we monitored the stability and performance of 3000 µm2 geometric surface area activated iridium oxide film (AIROF) electrodes within a wireless floating microelectrode array (WFMA) by measuring the voltage transient (VT) response through reverse telemetry. Eight WFMAs were assessed in vitro for 24 days, where n = 4 were pulsed continuously at 80 µA (16 nC/phase) and n = 4 remained in solution with no applied stimulation. Subsequently, twelve different WFMAs were implanted in visual cortex in n = 3 canine subjects (4 WFMAs each). After a 2-week recovery period, half of the electrodes in each of the twelve devices were pulsed continuously for 24 h at either 20, 40, 63, or 80 µA (200 µs pulse width, 100 Hz). VTs were recorded to track changes in the electrodes at set time intervals in both the saline and in vivo study. The VT response of AIROF electrodes remained stable during pulsing in saline over 24 days. Electrode polarization and driving voltage changed by less than 200 mV on average. The AIROF electrodes also maintained consistent performance, overall, during 24 h of pulsing in vivo. Four of the in vivo WFMA devices showed a change in polarization, access voltage, or driving voltage over time. However, no VT recordings indicated electrode failure, and the same trend was typically seen in both pulsed and unpulsed electrodes within the same device. Overall, accelerated stimulation testing in saline and in vivo indicated that AIROF electrodes in the WFMA were able to consistently deliver up to 16 nC per pulse and would be suitable for chronic clinical use.

The use of digital image correlation for measurement of strain fields in a novel wireless intraspinal microstimulation interface.

BACKGROUND: Intraspinal microstimulation (ISMS) has emerged as a promising neuromodulation technique for restoring standing and overground walking in individuals with spinal cord injury. Current and emerging ISMS implant designs connect the electrodes to the stimulator through lead wires that cross the dura mater. To reduce possible complications associated with transdural leads such as tethering and leakage of cerebrospinal fluid, we aim to develop a wireless, fully intradural ISMS implant based on our prior work in the cortex with the Wireless Floating Microelectrode Array (WFMA). Although we have extensive data about WFMA cortical stability, its mechanical and electrical stability in the spinal cord remains unknown. One of the quantifiable metrics to assess long-term implant stability is mechanical strain. OBJECTIVE: The aim of the current work is to develop a method to assess implant stability by measuring strain fields in a surrogate of the human spinal cord. METHODS: A physical model of the spinal cord was studied using an electromechanical testing apparatus, simulating typical spinal cord motion. Strain fields were digitally analyzed using an optical method known as digital image correlation (DIC). RESULTS: Displacement and strain were visualized using contour plots. The strain values in the vicinity of each WFMA device were significantly different from the strain values in the same locations in the control surrogate spinal cord. CONCLUSION: The results demonstrate that DIC can be used for in-vitro screening of intraspinal implants. Accurate optical strain measurements will enable researchers to optimize implant design over a wide range of motion conditions.

Wireless transmission of voltage transients from a chronically implanted neural stimulation device.

Objective.Consistent transmission of data from wireless neural devices is critical for monitoring the condition and performance of stimulation electrodes. To date, no wireless neural interface has demonstrated the ability to monitor the integrity of chronically implanted electrodes through wireless data transmission.Approach.In this work, we present a method for wirelessly recording the voltage transient (VT) response to constant-current, cathodic-first asymmetric pulsing from a microelectrode array. We implanted six wireless devices in rat sciatic nerve and wirelessly recorded VT measurements throughout a 38 week implantation period.Main results.Electrode maximum cathodic potential excursion (Emc), access voltage, and driving voltage (extracted from each VT) remained stable throughout the 38 week study period. Average Emc(from an applied +0.6 V interpulse bias) in response to 4.7µA, 200.2µs pulses was 267 ± 107 mV at week 1 post-implantation and 282 ± 52 mV at week 38 post-implantation. Access voltage for the same 4.7µA pulsing amplitude was 239 ± 65 mV at week 1 post-implantation and 268 ± 139 mV at week 38 post-implantation.Significance.The VT response recorded via reverse telemetry from the wireless microelectrode array did not significantly change over a 38 week implantation period and was similar to previously reported VTs from wired microelectrodes with the same geometry. Additionally, the VT response recorded wirelessly in phosphate buffered saline before and after device implantation appeared as expected, showing significantly less electrode polarization and smaller access voltage than the VT responsein vivo.

Effects of Varying Pulse Width and Frequency of Wireless Stimulation in Rat Sciatic Nerve.

Peripheral nerve stimulation is a commonly used method for assisting movements after spinal cord injury, stroke, traumatic brain injury, and other types of neurological damage or dysfunction. There are many different patterns of electrical stimulation used to accomplish movement. And so, our study investigated stimulation with a wireless floating microelectrode array (WFMA) in comparison to previously reported data on functional electrical stimulation. To determine the effect on hindlimb movement, we tested a range of frequencies and pulse widths using WFMAs that were implanted in the rat sciatic nerve for 38 weeks. Frequencies between 1 and 50 Hz did not change the minimum current amplitude required to elicit movement in the hindlimb. Increasing pulse width from 57.2 to 400.4 µs decreased the minimum current required but had an associated increase in total charge applied per pulse. Overall, the WFMA provides a stable wireless peripheral nerve interface suitable for functional electrical stimulation.Clinical Relevance- This work establishes the efficacy of various stimulation parameters for controlling movement with a wireless peripheral nerve stimulator.

Wireless microelectrode arrays for selective and chronically stable peripheral nerve stimulation for hindlimb movement.

Objective. Maximizing the stability of implanted neural interfaces will be critical to developing effective treatments for neurological and neuromuscular disorders. Our research aims to develop a stable neural interface using wireless communication and intrafascicular microelectrodes to provide highly selective stimulation of neural tissue.Approach. We implanted a wireless floating microelectrode array into the left sciatic nerve of six rats. Over a 38 week implantation period, we recorded stimulation thresholds and movements evoked at each implanted electrode. We also tracked each animal's response to sensory stimuli and performance on two different walking tasks.Main results. Presence of the microelectrode array inside the sciatic nerve did not cause any obvious motor or sensory deficits in the hindlimb. Visible movement in the hindlimb was evoked by stimulating the sciatic nerve with currents as low as 4.1µA. Thresholds for most of the 96 electrodes we implanted were below 20µA, and predictable recruitment of plantar flexion and dorsiflexion was achieved by stimulating rat sciatic nerve with the intrafascicular microelectrode array. Further, motor recruitment patterns for each electrode did not change significantly throughout the study.Significance. Incorporating wireless communication and a low-profile neural interface facilitated highly stable motor recruitment thresholds and fine motor control in the hindlimb throughout an extensive 9.5 month assessment in rodent peripheral nerve. Results of this study indicate that use of the wireless device tested here could be extended to other applications requiring selective neural stimulation and chronic implantation.

Toward the development of a color visual prosthesis.

Objective. All of the human prosthetic visual systems implanted so far have been achromatic. Schmidtet al(1996Brain119507-22) reported that at low stimulation intensities their subject reported that phosphenes usually had a specific hue, but when the stimulus intensity was increased, they desaturated to white. We speculate here that previous B/W prosthetic systems were unnecessarily over-stimulating the visual cortex to obtain white phosphenes, which may be why unexpected alterations in phosphenes and seizures were not an uncommon occurrence. A color prosthesis would have the advantage of being elicited by lower levels of stimulation, reducing the probability of causing epileptogenic responses.Approach.A 'hybrid' mode of stimulation is suggested, involving a combination of B/W and color stimulation, which could provide color information without reducing spatial resolution.Main results.Colors in the real world are spread along intensity and chromatic gradients.Significance.Software implementation strategies are discussed, as are the advantages and challenges for possible color prosthetic systems.

Selective Wireless Stimulation of Rat Sciatic Nerve.

Chronic stability of functional performance is a significant challenge to the success of implantable devices for neural stimulation and recording. Integrating wireless technology with typical microelectrode array designs is one approach that may reduce instances of mechanical failure and improve the long-term performance of neural devices. We have investigated the long-term stability of Wireless Floating Microelectrode Arrays (WMFAs) implanted in rat sciatic nerve, and their ability to selectively recruit muscles in the hind limb via neural stimulation. Thresholds as low as 4.1 µA were able to generate visible motion of the rear paw. Each implanted device (n=6) was able to selectively recruit plantar flexion and dorsiflexion of the rear paw, and selective stimulation of both movements was achieved throughout the study period. The evoked limb motion was electrode specific and was dependent on location within the fascicular structure of the nerve. Motor thresholds and movement patterns remained stable for more than 8 weeks after device implantation. No major changes in limb function were observed between the implanted and contralateral limb, or between implanted animals and control group animals. The results of this study show that WFMAs with intrafascicular electrodes implanted in a healthy peripheral nerve can provide stable and selective motor recruitment, without altering overall limb function.

Activated iridium oxide film (AIROF) electrodes for neural tissue stimulation.

OBJECTIVE: Iridium oxide films are commonly used as a high charge-injection electrode material in neural devices. Yet, few studies have performed in-depth assessments of material performance versus film thickness, especially for films grown on three-dimensional (instead of planar) metal surfaces in neutral pH electrolyte solutions. Further, few studies have investigated the driving voltage requirements for constant-current stimulation using activated iridium oxide (AIROF) electrodes, which will be a key constraint for future use in wirelessly powered neural devices. APPROACH: In this study, iridium microwire probes were activated by repeated potential pulsing in room temperature phosphate buffered saline (pH 7.1-7.3). Electrochemical measurements were recorded in three different electrolyte conditions for probes with different geometric surface areas (GSAs) as the AIROF thickness was increased. MAIN RESULTS: Maintaining an anodic potential bias during the inter-pulse interval was required for AIROF electrodes to deliver charge levels considered necessary for neural stimulation. Potential pulsing for 100-200 cycles was sufficient to achieve charge injection levels of 2.5 mC cm-2 (50 nC/phase in a biphasic pulse) in PBS with 2000 µm2 iridium probes. Increasing the electrode surface area to 3000 µm2 and 4000 µm2 significantly increased charge-injection capacity, reduced the driving voltage required to deliver a fixed amount of charge, and reduced polarization of the electrodes during constant-current pulsing. SIGNIFICANCE: This study establishes methods for choosing an activation protocol and a desired GSA for three-dimensional iridium electrodes suitable for neural tissue insertion and stimulation, and provides guidelines for evaluating electrochemical performance of AIROF using model saline solutions.

Harmonization of Outcomes and Vision Endpoints in Vision Restoration Trials: Recommendations from the International HOVER Taskforce.

Translational research in vision prosthetics, gene therapy, optogenetics, stem cell and other forms of transplantation, and sensory substitution is creating new therapeutic options for patients with neural forms of blindness. The technical challenges faced by each of these disciplines differ considerably, but they all face the same challenge of how to assess vision in patients with ultra-low vision (ULV), who will be the earliest subjects to receive new therapies. Historically, there were few tests to assess vision in ULV patients. In the 1990s, the field of visual prosthetics expanded rapidly, and this activity led to a heightened need to develop better tests to quantify end points for clinical studies. Each group tended to develop novel tests, which made it difficult to compare outcomes across groups. The common lack of validation of the tests and the variable use of controls added to the challenge of interpreting the outcomes of these clinical studies. In 2014, at the bi-annual International "Eye and the Chip" meeting of experts in the field of visual prosthetics, a group of interested leaders agreed to work cooperatively to develop the International Harmonization of Outcomes and Vision Endpoints in Vision Restoration Trials (HOVER) Taskforce. Under this banner, more than 80 specialists across seven topic areas joined an effort to formulate guidelines for performing and reporting psychophysical tests in humans who participate in clinical trials for visual restoration. This document provides the complete version of the consensus opinions from the HOVER taskforce, which, together with its rules of governance, will be posted on the website of the Henry Ford Department of Ophthalmology (www.artificialvision.org). Research groups or companies that choose to follow these guidelines are encouraged to include a specific statement to that effect in their communications to the public. The Executive Committee of the HOVER Taskforce will maintain a list of all human psychophysical research in the relevant fields of research on the same website to provide an overview of methods and outcomes of all clinical work being performed in an attempt to restore vision to the blind. This website will also specify which scientific publications contain the statement of certification. The website will be updated every 2 years and continue to exist as a living document of worldwide efforts to restore vision to the blind. The HOVER consensus document has been written by over 80 of the world's experts in vision restoration and low vision and provides recommendations on the measurement and reporting of patient outcomes in vision restoration trials.

Postmortem investigation of a human cortical visual prosthesis that was implanted for 36 years.

Objective: Postmortem analysis of the brain from a blind human subject who had a cortical visual prosthesis implanted for 36 years (Dobelle 2000 Asaio J. 46 3­9) Approach: This provided insight into the design requirements for a successful human cortical visual prosthesis by revealing, (a) unexpected rotation of the electrode array 25 to 40 degrees away from the midsagittal plane, thought to be due to the torque of the connecting cable, (b) degradation of the platinum electrodes, and (c) only partial coverage of the primary visual cortex by the rectangular array. The electrode array only overlapped with the anterior 45% of primary visual cortex (identified by the line of Gennari), largely missing the posterior foveal representation of visual cortex. Main results: A significantly greater proportions of electrodes outside of V1 elicited phosphenes than did electrodes within of V1. Histology did not reveal appreciable loss of neurons in cortex that surrounded the migrated array, perhaps due to the very slow rotation of this implant. Significance: This pioneering effort to develop a cortical visual prosthesis suggests that to maximize efficacy, the long-term effects of implanted alien materials on nervous tissue, and vice versa, need to be considered in detail, and that electrode array design considerations need to optimally match the electrodes to the patient's cortical anatomy. Modern pre-implant imaging can help optimize future implants by identifying the location and extent of bridging veins with MRI and even map the location of the V1/V2 border in vivo with PET.

Preparation of a neural electrode implantation device for in-vivo surgical use.

An instrument designed for the implantation of neural electrode array devices has been refined in preparation for use in cortical implantation procedures in non-human primates. This instrument has undergone extensive testing to ensure its successful first use in a live surgical setting. This work describes the modifications made to the instrument and the testing performed on it during that preparatory period as well as planned future modifications and augmentations.

Device for the implantation of neural electrode arrays.

Electrode arrays used in neural recording and stimulation applications must be implanted carefully to minimize damage to the underlying tissue. A device has been designed to improve a surgeon's control over implantation parameters including depth, insertion velocity, and insertion force. The device has been designed to operate without contacting tissue and to respond to tissue movements in real time during insertion. This device uses an electrical motor to drive electrode arrays into tissue and allows for the monitoring of and response to electrode depth during insertion. A prototype device has been constructed and tests have been performed to determine the velocity and force characteristics of the motor when inside the device housing. Future versions of the device will use a custom-designed motor with longer linear travel, which will allow the insertion device to be held farther from tissue while still ensuring proper array insertion.

Accelerated-stress reliability evaluation for an encapsulated wireless cortical stimulator.

In preparing a wireless cortical stimulator for use in the Intracortical Visual Prosthesis (ICVP) project at the Illinois Institute of Technology (IIT), an accelerated environmental stress test is being performed on prototype stimulator modules. Stimulator devices, containing a custom application specific integrated circuit (ASIC), and encapsulated with PDMS, were soaked in an autoclave chamber at 121°C and 100% relative humidity for more than 2200 hours with and without power supplied to the ASIC. Experimental results showed no physical degradation of the stimulator devices after soaking. Reverse telemetry that measures the stimulator internal power supply, recorded periodically over the entire test time, verified that the devices were electrically functioning, as designed, without deterioration. Taking into consideration other standard reliability test environments, the accelerated moisture resistance-biased autoclave testing duration of 2200 hours, as conducted in this study, overwhelms other less-severe test conditions and demonstrates long term stability of the proposed vision prosthesis device with proven thermo-mechanical and electrical robustness.

Low-power polling mode of the next-generation IMES2 implantable wireless EMG sensor.

The IMES1 Implantable MyoElectric Sensor device is currently in human clinical trials led by the Alfred Mann Foundation. The IMES is implanted in a residual limb and is powered wirelessly using a magnetic field. EMG signals resulting from the amputee's voluntary movement are amplified and transmitted wirelessly by the IMES to an external controller which controls movement of an external motorized prosthesis. Development of the IMES technology is on-going, producing the next-generation IMES2. Among various improvements, a new feature of the IMES2 is a low-power polling mode. In this low-power mode, the IMES2 power consumption can be dramatically reduced when the limb is inactive through the use of a polled sampling. With the onset of EMG activity, the IMES2 system can switch to the normal higher sample rate to allow the acquisition of high-fidelity EMG data for prosthesis control.

Multichannel wireless ECoG array ASIC devices.

Surgical resection of epileptogenic foci is often a beneficial treatment for patients suffering debilitating seizures arising from intractable epilepsy [1], [2], [3]. Electrodes placed subdurally on the surface of the brain in the form of an ECoG array is one of the multiple methods for localizing epileptogenic zones for the purpose of defining the region for surgical resection. Currently, transcutaneous wires from ECoG grids limit the duration of time that implanted grids can be used for diagnosis. A wireless ECoG recording and stimulation system may be a solution to extend the diagnostic period. To avoid the transcutaneous connections, a 64-channel wireless silicon recording/stimulating ASIC was developed as the electronic component of a wireless ECoG array that uses SIROF electrodes on a polyimide substrate[4]. Here we describe two new ASIC devices that have been developed and tested as part of the on-going wireless ECoG system design.

Identification and quantification of electrical leakage pathways in floating microelectrode arrays.

The long-term reliability of neural recording and stimulation electrode arrays is becoming the limiting factor for neural interfaces. For effective electrode design, electrical connection to the surrounding neural tissue and fluid should be limited to the electrode tips, with all other leakage currents minimized. It is the goal of this study to identify and quantify electrical leakage within commercially available floating microelectrode arrays (FMAs). Both short term and accelerated stress tests were performed on entire FMAs, as well as on individual electrodes typical of such arrays. Preliminary results of these tests indicate that leakage currents are present due to water penetration of their insulation layer initially, but that prolonged water exposure at high temperature may seal the defects that cause these currents. SEM photos taken of the electrode shafts show extensive defect regions that may correlate with the test data.

Electrical performance of penetrating microelectrodes chronically implanted in cat cortex.

Penetrating microelectrode arrays with 2000 µm (2) sputtered iridium oxide (SIROF) electrode sites were implanted in cat cerebral cortex, and their long-term electrochemical performance evaluated in vivo by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and current pulsing. Measurements were made from days 33 to 328 postimplantation. The CV-defined charge storage capacity, measured at 50 mV/s, increased linearly with time over the course of implantation for two arrays and was unchanged for one array. A modest decrease in 1 kHz impedance was also observed. These results suggest an ongoing increase in the apparent electrochemical surface area of the electrodes, which is attributed to electrical leakage pathways arising from cracking of Parylene insulation observed by SEM of explanted arrays. During current pulsing with a 0.0 V interpulse bias, the electrodes readily delivered 8 nC/phase in vitro, but some channels approached or exceeded the water reduction potential during in vivo pulsing. The charge injection capacity in vivo increased linearly with the interpulse bias (0-0.6 V Ag\vert AgCl) from 11.5 to 21.8 nC/ph and with pulse width (150-500 µs) from 8.8 to 14 nC/ph (at 0.0 V bias). These values are lower than those determined from measurements in buffered physiological saline, emphasizing the importance of in vivo measurements in assessing chronic electrode performance. The consequence of current leakage pathways on the charge-injection measurements is also discussed.

A power and data link for a wireless-implanted neural recording system.

A wireless cortical neural recording system with a miniature-implanted package is needed in a variety of neuroscience and biomedical applications. Toward that end, we have developed a transcutaneous two-way communication and power system for wireless neural recording. Wireless powering and forward data transmission (into the body) at 1.25 Mbps is achieved using a frequency-shift keying modulated class E converter. The reverse telemetry (out of the body) carrier frequency is generated using an integer-N phase-locked loop, providing the necessary wideband data link to support simultaneous reverse telemetry from multiple implanted devices on separate channels. Each channel is designed to support reverse telemetry with a data rate in excess of 3 Mbps, which is sufficient for our goal of streaming 16 channels of raw neural data. We plan to incorporate this implantable power and telemetry system in a 1-cm diameter single-site cortical neural recording implant.

An implantable neural stimulator for intraspinal microstimulation.

This paper reports on a wireless stimulator device for use in animal experiments as part of an ongoing investigation into intraspinal stimulation (ISMS) for restoration of walking in humans with spinal cord injury. The principle behind using ISMS is the activation of residual motor-control neural networks within the spinal cord ventral horn below the level of lesion following a spinal cord injury. The attractiveness to this technique is that a small number of electrodes can be used to induce bilateral walking patterns in the lower limbs. In combination with advanced feedback algorithms, ISMS has the potential to restore walking for distances that exceed that produced by other types of functional electrical stimulation. Recent acute animal experiments have demonstrated the feasibility of using ISMS to produce the coordinated walking patterns. Here we described a wireless implantable stimulation system to be used in chronic animal experiments and for providing the basis for a system suitable for use in humans. Electrical operation of the wireless system is described, including a demonstration of reverse telemetry for monitoring the stimulating electrode voltages.