Significantly reduced inflammatory foreign-body-response to neuroimplants and improved recording performance in young compared to adult rats.

The multicellular inflammatory encapsulation of implanted intracortical multielectrode arrays (MEA) is associated with severe deterioration of their field potentials' (FP) recording performance, which thus limits the use of brain implants in basic research and clinical applications. Therefore, extensive efforts have been made to identify the conditions in which the inflammatory foreign body response (FBR) is alleviated, or to develop methods to mitigate the formation of the inflammatory barrier. Here, for the first time, we show that (1) in young rats (74±8 gr, 4 weeks old at the onset of the experiments), cortical tissue recovery following MEA implantation proceeds with ameliorated inflammatory scar as compared to adult rats (242 ± 18 gr, 9 weeks old at the experimental onset); (2) in contrast to adult rats in which the Colony Stimulating factor 1 Receptor (CSF1R) antagonist chow eliminated ∼95% of the cortical microglia but not microglia adhering to the implant surfaces, in young rats the microglia adhering to the implant were eliminated along with the parenchymal microglia population. The removal of microglia adhering to the implant surfaces was correlated with improved recording performance by in-house fabricated Perforated Polyimide MEA Platforms (PPMP). These results support the hypothesis that microglia adhering to the surface of the electrodes, rather than the multicellular inflammatory scar, is the major underlying mechanism that deteriorates implant recording performance, and that young rats provide an advantageous model to study months-long, multisite electrophysiology in freely behaving rats. STATEMENT OF SIGNIFICANCE: Multisite electrophysiological recordings and stimulation devices play central roles in basic brain research and medical applications. The insertion of multielectrode-array platforms into the brain's parenchyma unavoidably injures the tissue, and initiates a multicellular inflammatory cascade culminating in the formation of an encapsulating scar tissue (the foreign body response-FBR). The dominant view, which directs most current research efforts to mitigate the FBR, holds that the FBR is the major hurdle to effective electrophysiological use of neuroprobes. By contrast, this report demonstrates that microglia adhering to the surface of a neuroimplants, rather than the multicellular FBR, underlie the performance deterioration of neuroimplants. These findings pave the way to the development of novel and focused strategies to overcome the functional deterioration of neuroimplants.

Chronic nerve health following implantation of femoral nerve cuff electrodes.

BACKGROUND: Peripheral nerve stimulation with implanted nerve cuff electrodes can restore standing, stepping and other functions to individuals with spinal cord injury (SCI). We performed the first study to evaluate the clinical electrodiagnostic changes due to electrode implantation acutely, chronic presence on the nerve peri- and post-operatively, and long-term delivery of electrical stimulation. METHODS: A man with bilateral lower extremity paralysis secondary to cervical SCI sustained 5 years prior to enrollment received an implanted standing neuroprosthesis including composite flat interface nerve electrodes (C-FINEs) electrodes implanted around the proximal femoral nerves near the inguinal ligaments. Electromyography quantified neurophysiology preoperatively, intraoperatively, and through 1 year postoperatively. Stimulation charge thresholds, evoked knee extension moments, and weight distribution during standing quantified neuroprosthesis function over the same interval. RESULTS: Femoral compound motor unit action potentials increased 31% in amplitude and 34% in area while evoked knee extension moments increased significantly (p < 0.01) by 79% over 1 year of rehabilitation with standing and quadriceps exercises. Charge thresholds were low and stable, averaging 19.7 nC ± 6.2 (SEM). Changes in saphenous nerve action potentials and needle electromyography suggested minor nerve irritation perioperatively. CONCLUSIONS: This is the first human trial reporting acute and chronic neurophysiologic changes due to application of and stimulation through nerve cuff electrodes. Electrodiagnostics indicated preserved nerve health with strengthened responses following stimulated exercise. Temporary electrodiagnostic changes suggest minor nerve irritation only intra- and peri-operatively, not continuing chronically nor impacting function. These outcomes follow implantation of a neuroprosthesis enabling standing and demonstrate the ability to safely implant electrodes on the proximal femoral nerve close to the inguinal ligament. We demonstrate the electrodiagnostic findings that can be expected from implanting nerve cuff electrodes and their time-course for resolution, potentially applicable to prostheses modulating other peripheral nerves and functions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01923662 , retrospectively registered August 15, 2013.

Improving Safety of MRI in Patients with Deep Brain Stimulation Devices.

MRI is a valuable clinical and research tool for patients undergoing deep brain stimulation (DBS). However, risks associated with imaging DBS devices have led to stringent regulations, limiting the clinical and research utility of MRI in these patients. The main risks in patients with DBS devices undergoing MRI are heating at the electrode tips, induced currents, implantable pulse generator dysfunction, and mechanical forces. Phantom model studies indicate that electrode tip heating remains the most serious risk for modern DBS devices. The absence of adverse events in patients imaged under DBS vendor guidelines for MRI demonstrates the general safety of MRI for patients with DBS devices. Moreover, recent work indicates that-given adequate safety data-patients may be imaged outside these guidelines. At present, investigators are primarily focused on improving DBS device and MRI safety through the development of tools, including safety simulation models. Existing guidelines provide a standardized framework for performing safe MRI in patients with DBS devices. It also highlights the possibility of expanding MRI as a tool for research and clinical care in these patients going forward.

Histological evaluation of flexible neural implants; flexibility limit for reducing the tissue response?

OBJECTIVE: Flexible neural probes are hypothesized to reduce the chronic foreign body response (FBR) mainly by reducing the strain-stress caused by an interplay between the tethered probe and the brain's micromotion. However, a large discrepancy of Young's modulus still exists (3-6 orders of magnitude) between the flexible probes and the brain tissue. This raises the question of whether we need to bridge this gap; would increasing the probe flexibility proportionally reduce the FBR? APPROACH: Using novel off-stoichiometry thiol-enes-epoxy (OSTE+) polymer probes developed in our previous work, we quantitatively evaluated the FBR to four types of probes with different softness: silicon (~150 GPa), polyimide (1.5 GPa), OSTE+Hard (300 MPa), and OSTE+Soft (6 MPa). MAIN RESULTS: We observed a significant reduction in the fluorescence intensity of biomarkers for activated microglia/macrophages and blood-brain barrier (BBB) leakiness around the three soft polymer probes compared to the silicon probe, both at 4 weeks and 8 weeks post-implantation. However, we did not observe any consistent differences in the biomarkers among the polymer probes. SIGNIFICANCE: The results suggest that the mechanical compliance of neural probes can mediate the degree of FBR, but its impact diminishes after a hypothetical threshold level. This infers that resolving the mechanical mismatch alone has a limited effect on improving the lifetime of neural implants.

Functional remodeling of subtype-specific markers surrounding implanted neuroprostheses.

Microelectrode arrays implanted in the brain are increasingly used for the research and treatment of intractable neurological disease. However, local neuronal loss and glial encapsulation are known to interfere with effective integration and communication between implanted devices and brain tissue, where these observations are typically based on assessments of broad neuronal and astroglial markers. However, both neurons and astrocytes comprise heterogeneous cellular populations that can be further divided into subclasses based on unique functional and morphological characteristics. In this study, we investigated whether or not device insertion causes alterations in specific subtypes of these cells. We assessed the expression of both excitatory and inhibitory markers of neurotransmission (vesicular glutamate and GABA transporters, VGLUT1 and VGAT, respectively) surrounding single-shank Michigan-style microelectrode arrays implanted in the motor cortex of adult rats by use of quantitative immunohistochemistry. We found a pronounced shift from significantly elevated VGLUT1 within the initial days following implantation to relatively heightened VGAT by the end of the 4-wk observation period. Unexpectedly, we observed VGAT positivity in a subset of reactive astrocytes during the first week of implantation, indicating heterogeneity in early-responding encapsulating glial cells. We coupled our VGLUT1 data with the evaluation of a second marker of excitatory neurons (CamKiiα); the results closely paralleled each other and underscored a progression from initially heightened to subsequently weakened excitatory tone in the neural tissue proximal to the implanted electrode interface (within 40 µm). Our results provide new evidence for subtype-specific remodeling surrounding brain implants that inform observations of suboptimal integration and performance.NEW & NOTEWORTHY We report novel changes in the local expression of excitatory and inhibitory synaptic markers surrounding microelectrode arrays implanted in the motor cortex of rats, where a progressive shift toward increased inhibitory tone was observed over the 4-wk observation period. The result was driven by declining glutamate transporter expression (VGLUT1) in parallel with increasing GABA transporter expression (VGAT) over time, where a reactive VGAT+ astroglial subtype made an unexpected contribution to our findings.

The Utility of the MAUDE Database for Osseointegrated Auditory Implants.

OBJECTIVE: To determine the utility of Manufacturer and User Friendly Device Experience (MAUDE) database in studying osseointegrated auditory implant (OAI)-related complications. METHODS: The MAUDE database was searched for all reports involving OAIs (ie, Baha, Ponto, Sophono). Complications were classified into 1 or more of 6 categories-implant, abutment, processor, skin, surgery, and other. Subcategories were generated to prevent overgeneralization. Other variables recorded included date of report, number of complications per report, manufacturer, and time from complication to report. RESULTS: Over the study period, there were 269 complications listed from 238 reports divided into the following categories: implant related (n = 145), abutment related (n = 16), processor related (n = 13), skin and soft tissue related (n = 79), surgery related (n = 11), and other (n = 5). No demographic data were available. There were no discernible trends from the data, and when compared to published literature, MAUDE data appear to under- or misrepresent complications. CONCLUSION: The MAUDE database is limited in its design and given fairly disparate reporting quality may not be ideally suited for quantifying risks of OAIs. These findings suggest the necessity for a substantially improved central registry for otologic implants and highlight the need for further research to investigate the root causes of their associated complication.

A preliminary comparison of myoelectric and cyclic control of an implanted neuroprosthesis to modulate gait speed in incomplete SCI.

OBJECTIVE: Explore whether electromyography (EMG) control of electrical stimulation for walking after incomplete spinal cord injury (SCI) can affect ability to modulate speed and alter gait spatial-temporal parameters compared to cyclic repetition of pre-programmed stimulation. DESIGN: Single case study with subject acting as own concurrent control. Setting Hospital-based biomechanics laboratory. PARTICIPANTS: Single subject with C6 AIS D SCI using an implanted neuroprosthesis for walking. Interventions Lower extremity muscle activation via an implanted system with two different control methods: (1) pre-programmed pattern of stimulation, and (2) EMG-controlled stimulation based on signals from the gastrocnemius and quadriceps. OUTCOME MEASURES: Gait speed, distance, and subjective rating of difficulty during 2-minute walks. Range of walking speeds and associated cadences, stride lengths, stride times, and double support times during quantitative gait analysis. RESULTS: EMG control resulted in statistically significant increases in both walking speed and distance (P < 0.001) over cyclic stimulation during 2-minute walks. Maximum walking speed with EMG control (0.48 m/second) was significantly (P < 0.001) faster than the fastest automatic pattern (0.39 m/second), with increased cadence and decreased stride and double support times (P < 0.000) but no change in stride length (z = -0.085; P = 0.932). The slowest walking with EMG control (0.25 m/second) was virtually indistinguishable from the slowest with automatic cycling (z = -0.239; P = 0.811). CONCLUSION: EMG control can increase the ability to modulate comfortable walking speed over pre-programmed cyclic stimulation. While control methods did not differ at the lowest speed, EMG-triggered stimulation allowed significantly faster walking than cyclic stimulation. The expanded range of available walking speeds could permit users to better avoid obstacles and naturally adapt to various environments. Further research is required to definitively determine the robustness, generalizability, and functional implications of these results.

Effects of caspase-1 knockout on chronic neural recording quality and longevity: insight into cellular and molecular mechanisms of the reactive tissue response.

Chronic implantation of microelectrodes into the cortex has been shown to lead to inflammatory gliosis and neuronal loss in the microenvironment immediately surrounding the probe, a hypothesized cause of neural recording failure. Caspase-1 (aka Interleukin 1ß converting enzyme) is known to play a key role in both inflammation and programmed cell death, particularly in stroke and neurodegenerative diseases. Caspase-1 knockout (KO) mice are resistant to apoptosis and these mice have preserved neurologic function by reducing ischemia-induced brain injury in stroke models. Local ischemic injury can occur following neural probe insertion and thus in this study we investigated the hypothesis that caspase-1 KO mice would have less ischemic injury surrounding the neural probe. In this study, caspase-1 KO mice were implanted with chronic single shank 3 mm Michigan probes into V1m cortex. Electrophysiology recording showed significantly improved single-unit recording performance (yield and signal to noise ratio) of caspase-1 KO mice compared to wild type C57B6 (WT) mice over the course of up to 6 months for the majority of the depth. The higher yield is supported by the improved neuronal survival in the caspase-1 KO mice. Impedance fluctuates over time but appears to be steadier in the caspase-1 KO especially at longer time points, suggesting milder glia scarring. These findings show that caspase-1 is a promising target for pharmacologic interventions.

The effect of micro-ECoG substrate footprint on the meningeal tissue response.

OBJECTIVE: There is great interest in designing implantable neural electrode arrays that maximize function while minimizing tissue effects and damage. Although it has been shown that substrate geometry plays a key role in the tissue response to intracortically implanted, penetrating neural interfaces, there has been minimal investigation into the effect of substrate footprint on the tissue response to surface electrode arrays. This study investigates the effect of micro-electrocorticography (micro-ECoG) device geometry on the longitudinal tissue response. APPROACH: The meningeal tissue response to two micro-ECoG devices with differing geometries was evaluated. The first device had each electrode site and trace individually insulated, with open regions in between, while the second device had a solid substrate, in which all 16 electrode sites were embedded in a continuous insulating sheet. These devices were implanted bilaterally in rats, beneath cranial windows, through which the meningeal tissue response was monitored for one month after implantation. Electrode site impedance spectra were also monitored during the implantation period. MAIN RESULTS: It was observed that collagenous scar tissue formed around both types of devices. However, the distribution of the tissue growth was different between the two array designs. The mesh devices experienced thick tissue growth between the device and the cranial window, and minimal tissue growth between the device and the brain, while the solid device showed the opposite effect, with thick tissue forming between the brain and the electrode sites. SIGNIFICANCE: These data suggest that an open architecture device would be more ideal for neural recording applications, in which a low impedance path from the brain to the electrode sites is critical for maximum recording quality.

Fluorescein angiographic findings in eyes of patients with a subretinal electronic implant.

PURPOSE: One approach for restoring vision in end-stage hereditary retinal diseases is implantation of a subretinal microphotodiode array. We analyzed retinal fluorescein angiography findings of the implant area. METHODS: In this pilot study, patients (n = 11; 10 men, one woman; ages 45.2 ± 8.7 years), with visual acuity of light perception or worse resulting from a hereditary retinal degenerative disease, received active electronic subretinal visual implants. Implants were removed after 4 weeks (n = 7 subjects) or 4 months (n = 4 subjects). Following implantation, regular fluorescein angiography was performed. Regions of retinal capillary loss, microaneurysms, capillary alterations, neovascularization and leakage over the implant were scored at time points T1 (days 1-14), T2 (days 15-28) and T3 (months 3-4). Occurrence and changes of fluorescein angiographic phenomena are reported. RESULTS: In terms of the number of patients in whom retinal alterations were observed (compared to available images) the occurences of the angiographic phenomena (for time points T1, T2 and T3, respectively) were as follows: regions of capillary loss (five of seven, 10 of 11 and five of five patients), microaneurysms (0 of seven, two of 11 and three of five patients), calibre alterations of the capillaries (three of seven, eight of 11 and five of five patients), retinal neovascularization (one of seven, one of 11 and 0 of five) and leakage (three of seven, seven of 11 and four of five). The Friedman test revealed no significant changes in capillary loss, calibre alteration of the capillaries, neovascularization or leakage. Microaneurysms increased significantly (p = 0.037). CONCLUSIONS: Subretinal visual implants lead to increased capillary microaneurysms, a possible compensatory mechanism following recovery of inner retinal activity. There were no significant changes in capillary loss, calibre alteration of the capillaries, retinal neovascularization and leakage at 4 months. Further study will determine whether and to what degree long-term vascular changes are affected by the surgical procedure, the implant itself and/or recovery of retinal neuronal activity.

Longitudinal performance of a surgically implanted neuroprosthesis for lower-extremity exercise, standing, and transfers after spinal cord injury.

OBJECTIVE: To investigate the longitudinal performance of a surgically implanted neuroprosthesis for lower-extremity exercise, standing, and transfers after spinal cord injury. DESIGN: Case series. SETTING: Research or outpatient physical therapy departments of 4 academic hospitals. PARTICIPANTS: Subjects (N=15) with thoracic or low cervical level spinal cord injuries who had received the 8-channel neuroprosthesis for exercise and standing. INTERVENTION: After completing rehabilitation with the device, the subjects were discharged to unrestricted home use of the system. A series of assessments were performed before discharge and at a follow-up appointment approximately 1 year later. MAIN OUTCOME MEASURES: Neuroprosthesis usage, maximum standing time, body weight support, knee strength, knee fatigue index, electrode stability, and component survivability. RESULTS: Levels of maximum standing time, body weight support, knee strength, and knee fatigue index were not statistically different from discharge to follow-up (P>.05). Additionally, neuroprosthesis usage was consistent with subjects choosing to use the system on approximately half of the days during each monitoring period. Although the number of hours using the neuroprosthesis remained constant, subjects shifted their usage to more functional standing versus more maintenance exercise, suggesting that the subjects incorporated the neuroprosthesis into their lives. Safety and reliability of the system were demonstrated by electrode stability and a high component survivability rate (>90%). CONCLUSIONS: This group of 15 subjects is the largest cohort of implanted lower-extremity neuroprosthetic exercise and standing system users. The safety and efficiency data from this group, and acceptance of the neuroprosthesis as demonstrated by continued usage, indicate that future efforts toward commercialization of a similar device may be warranted.

Effects of vestibular prosthesis electrode implantation and stimulation on hearing in rhesus monkeys.

To investigate the effects of vestibular prosthesis electrode implantation and activation on hearing in rhesus monkeys, we measured auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE) in four rhesus monkeys before and after unilateral implantation of vestibular prosthesis electrodes in each of 3 left semicircular canals (SCC). Each of the 3 left SCCs were implanted with electrodes via a transmastoid approach. Right ears, which served as controls, were not surgically manipulated. Hearing tests were conducted before implantation (BI) and then 4 weeks post-implantation both without electrical stimulation (NS) and with electrical stimulation (S). During the latter condition, prosthetic electrical stimuli encoding 3 dimensions of head angular velocity were delivered to the 3 ampullary branches of the left vestibular nerve via each of 3 electrode pairs of a multichannel vestibular prosthesis. Electrical stimuli comprised charge-balanced biphasic pulses at a baseline rate of 94 pulses/s, with pulse frequency modulated from 48 to 222 pulses/s by head angular velocity. ABR hearing thresholds to clicks and tone pips at 1, 2, and 4 kHz increased by 5-10 dB from BI to NS and increased another ∼5 dB from NS to S in implanted ears. No significant change was seen in right ears. DPOAE amplitudes decreased by 2-14 dB from BI to NS in implanted ears. There was a slight but insignificant decrease of DPOAE amplitude and a corresponding increase of DPOAE/Noise floor ratio between NS and S in implanted ears. Vestibular prosthesis electrode implantation and activation have small but measurable effects on hearing in rhesus monkeys. Coupled with the clinical observation that patients with cochlear implants only rarely exhibit signs of vestibular injury or spurious vestibular nerve stimulation, these results suggest that although implantation and activation of multichannel vestibular prosthesis electrodes in human will carry a risk of hearing loss, that loss is not likely to be severe.