Penetrating Microelectrode Arrays Research Articles

Highly stretchable and customizable microneedle electrode arrays for intramuscular electromyography.

Stretchable three-dimensional (3D) penetrating microelectrode arrays have potential utility in various fields, including neuroscience, tissue engineering, and wearable bioelectronics. These 3D microelectrode arrays can penetrate and conform to dynamically deforming tissues, thereby facilitating targeted sensing and stimulation of interior regions in a minimally invasive manner. However, fabricating custom stretchable 3D microelectrode arrays presents material integration and patterning challenges. In this study, we present the design, fabrication, and applications of stretchable microneedle electrode arrays (SMNEAs) for sensing local intramuscular electromyography signals ex vivo. We use a unique hybrid fabrication scheme based on laser micromachining, microfabrication, and transfer printing to enable scalable fabrication of individually addressable SMNEA with high device stretchability (60 to 90%). The electrode geometries and recording regions, impedance, array layout, and length distribution are highly customizable. We demonstrate the use of SMNEAs as bioelectronic interfaces in recording intramuscular electromyography from various muscle groups in the buccal mass of Aplysia.

Interictal discharge traveling waves recorded from stereoelectroencephalography electrodes.

Interictal epileptiform discharges (IEDs) are intermittent high-amplitude electrical signals that occur between seizures. They have been shown to propagate through the brain as traveling waves when recorded with epicortical grid-type electrodes and small penetrating microelectrode arrays. However, little work has been done to translate experimental IED analyses to more clinically relevant platforms such as stereoelectroencephalography (SEEG). In this pilot study, the authors aimed to define a computational method to identify and characterize IEDs recorded from clinical SEEG electrodes and leverage the directionality of IED traveling waves to localize the seizure onset zone (SOZ). Continuous SEEG recordings from 15 patients with medically refractory epilepsy were collected, and IEDs were detected by identifying overlapping peaks of a minimum prominence. IED pathways of propagation were defined and compared to the SOZ location determined by a clinical neurologist based on the ictal recordings. For further analysis of the IED pathways of propagation, IED detections were divided into triplets, defined as a set of 3 consecutive contacts within the same IED detection. Univariate and multivariate linear regression models were employed to associate IED characteristics with colocalization to the SOZ. A median (range) of 22.6 (4.4-183.9) IEDs were detected per hour from 15 patients over a mean of 23.2 hours of recording. Depending on the definition of the SOZ, a median (range) of 20.8% (0.0%-54.5%) to 62.1% (19.2%-99.4%) of IEDs per patient traversed the SOZ. IEDs passing through the SOZ followed discrete pathways that had little overlap with those of the IEDs passing outside the SOZ. Contact triplets that occurred more than once were significantly more likely to be detected in an IED passing through the SOZ (p < 0.001). Per our multivariate model, patients with a greater proportion of IED traveling waves had a significantly greater proportion of IEDs that localized to the SOZ (β = 0.64, 95% CI 0.01-1.27, p = 0.045). By using computational methods, IEDs can be meaningfully detected from clinical-grade SEEG recordings of patients with epilepsy. In some patients, a high proportion of IEDs are traveling waves according to multiple metrics that colocalize to the SOZ, offering hope that IED detection, with further refinement, could serve as an alternative method for SOZ localization.

Behavioral paradigm for the evaluation of stimulation-evoked somatosensory perception thresholds in rats.

Intracortical microstimulation (ICMS) of the somatosensory cortex via penetrating microelectrode arrays (MEAs) can evoke cutaneous and proprioceptive sensations for restoration of perception in individuals with spinal cord injuries. However, ICMS current amplitudes needed to evoke these sensory percepts tend to change over time following implantation. Animal models have been used to investigate the mechanisms by which these changes occur and aid in the development of new engineering strategies to mitigate such changes. Non-human primates are commonly the animal of choice for investigating ICMS, but ethical concerns exist regarding their use. Rodents are a preferred animal model due to their availability, affordability, and ease of handling, but there are limited choices of behavioral tasks for investigating ICMS. In this study, we investigated the application of an innovative behavioral go/no-go paradigm capable of estimating ICMS-evoked sensory perception thresholds in freely moving rats. We divided animals into two groups, one receiving ICMS and a control group receiving auditory tones. Then, we trained the animals to nose-poke - a well-established behavioral task for rats - following either a suprathreshold ICMS current-controlled pulse train or frequency-controlled auditory tone. Animals received a sugar pellet reward when nose-poking correctly. When nose-poking incorrectly, animals received a mild air puff. After animals became proficient in this task, as defined by accuracy, precision, and other performance metrics, they continued to the next phase for perception threshold detection, where we varied the ICMS amplitude using a modified staircase method. Finally, we used non-linear regression to estimate perception thresholds. Results indicated that our behavioral protocol could estimate ICMS perception thresholds based on ~95% accuracy of rat nose-poke responses to the conditioned stimulus. This behavioral paradigm provides a robust methodology for evaluating stimulation-evoked somatosensory percepts in rats comparable to the evaluation of auditory percepts. In future studies, this validated methodology can be used to study the performance of novel MEA device technologies on ICMS-evoked perception threshold stability using freely moving rats or to investigate information processing principles in neural circuits related to sensory perception discrimination.

In vivo spatiotemporal dynamics of astrocyte reactivity following neural electrode implantation

Brain computer interfaces (BCIs), including penetrating microelectrode arrays, enable both recording and stimulation of neural cells. However, device implantation inevitably causes injury to brain tissue and induces a foreign body response, leading to reduced recording performance and stimulation efficacy. Astrocytes in the healthy brain play multiple roles including regulating energy metabolism, homeostatic balance, transmission of neural signals, and neurovascular coupling. Following an insult to the brain, they are activated and gather around the site of injury. These reactive astrocytes have been regarded as one of the main contributors to the formation of a glial scar which affects the performance of microelectrode arrays. This study investigates the dynamics of astrocytes within the first 2 weeks after implantation of an intracortical microelectrode into the mouse brain using two-photon microscopy. From our observation astrocytes are highly dynamic during this period, exhibiting patterns of process extension, soma migration, morphological activation, and device encapsulation that are spatiotemporally distinct from other glial cells, such as microglia or oligodendrocyte precursor cells. This detailed characterization of astrocyte reactivity will help to better understand the tissue response to intracortical devices and lead to the development of more effective intervention strategies to improve the functional performance of neural interfacing technology.

Scalable Thousand Channel Penetrating Microneedle Arrays on Flex for Multimodal and Large Area Coverage BrainMachine Interfaces.

The Utah array powers cutting-edge projects for restoration of neurological function, such as BrainGate, but the underlying electrode technology has itself advanced little in the last three decades. Here, advanced dual-side lithographic microfabrication processes is exploited to demonstrate a 1024-channel penetrating silicon microneedle array (SiMNA) that is scalable in its recording capabilities and cortical coverage and is suitable for clinical translation. The SiMNA is the first penetrating microneedle array with a flexible backing that affords compliancy to brain movements. In addition, the SiMNA is optically transparent permitting simultaneous optical and electrophysiological interrogation of neuronal activity. The SiMNA is used to demonstrate reliable recordings of spontaneous and evoked field potentials and of single unit activity in chronically implanted mice for up to 196 days in response to optogenetic and to whisker air-puff stimuli. Significantly, the 1024-channel SiMNA establishes detailed spatiotemporal mapping of broadband brain activity in rats. This novel scalable and biocompatible SiMNA with its multimodal capability and sensitivity to broadband brain activity will accelerate the progress in fundamental neurophysiological investigations and establishes a new milestone for penetrating and large area coverage microelectrode arrays for brain-machine interfaces.

Long-term in-vivo recording performance of flexible penetrating microelectrode arrays

Objective. Neural interfaces are an essential tool to enable the human body to directly communicate with machines such as computers or prosthetic robotic arms. Since invasive electrodes can be located closer to target neurons, they have advantages such as precision in stimulation and high signal-to-noise ratio (SNR) in recording, while they often exhibit unstable performance in long-term in-vivo implantation because of the tissue damage caused by the electrodes insertion. In the present study, we investigated the electrical functionality of flexible penetrating microelectrode arrays (FPMAs) up to 3 months in in-vivo conditions. Approach. The in-vivo experiment was performed by implanting FPMAs in five rats. The in-vivo impedance as well as the action potential (AP) amplitude and SNR were analyzed over weeks. Additionally, APs were tracked over time to investigate the possibility of single neuron recording. Main results. It was observed that the FPMAs exhibited dramatic increases in impedance for the first 4 weeks after implantation, accompanied by decreases in AP amplitude. However, the increase/decrease in AP amplitude was always accompanied by the increase/decrease in background noise, resulting in quite consistently maintained SNRs. After 4 weeks of implantation, we observed two distinctive issues regarding long-term implantation, each caused by chronic tissue responses or by the delamination of insulation layer. The results demonstrate that the FPMAs successfully recorded neuronal signals up to 12 weeks, with very stably maintained SNRs, reduced by only 16.1% on average compared to the first recordings, although biological tissue reactions or physical degradation of the FPMA were present. Significance. The fabricated FPMAs successfully recorded intracortical signals for 3 months. The SNR was maintained up to 3 months and the chronic function of FPMA was comparable with other silicon based implantable electrodes.

A 3D flexible neural interface based on a microfluidic interconnection cable capable of chemical delivery

The demand for multifunctional neural interfaces has grown due to the need to provide a better understanding of biological mechanisms related to neurological diseases and neural networks. Direct intracerebral drug injection using microfluidic neural interfaces is an effective way to deliver drugs to the brain, and it expands the utility of drugs by bypassing the blood–brain barrier (BBB). In addition, uses of implantable neural interfacing devices have been challenging due to inevitable acute and chronic tissue responses around the electrodes, pointing to a critical issue still to be overcome. Although neural interfaces comprised of a collection of microneedles in an array have been used for various applications, it has been challenging to integrate microfluidic channels with them due to their characteristic three-dimensional structures, which differ from two-dimensionally fabricated shank-type neural probes. Here we present a method to provide such three-dimensional needle-type arrays with chemical delivery functionality. We fabricated a microfluidic interconnection cable (µFIC) and integrated it with a flexible penetrating microelectrode array (FPMA) that has a 3-dimensional structure comprised of silicon microneedle electrodes supported by a flexible array base. We successfully demonstrated chemical delivery through the developed device by recording neural signals acutely from in vivo brains before and after KCl injection. This suggests the potential of the developed microfluidic neural interface to contribute to neuroscience research by providing simultaneous signal recording and chemical delivery capabilities.

Both high fat and high carbohydrate diets impair vagus nerve signaling of satiety

Obesity remains prevalent in the US. One potential treatment is vagus nerve stimulation (VNS), which activates the sensory afferents innervating the stomach that convey stomach volume and establish satiety. However, current VNS approaches and stimulus optimization could benefit from additional understanding of the underlying neural response to stomach distension. In this study, obesity-prone Sprague Dawley rats consumed a standard, high-carbohydrate, or high-fat diet for several months, leading to diet-induced obesity in the latter two groups. Under anesthesia, the neural activity in the vagus nerve was recorded with a penetrating microelectrode array while the stomach was distended with an implanted balloon. Vagal tone during distension was compared to baseline tone prior to distension. Responses were strongly correlated with stomach distension, but the sensitivity to distension was significantly lower in animals that had been fed the nonstandard diets. The results indicate that both high fat and high carbohydrate diets impair vagus activity.

Advances in Carbon-Based Microfiber Electrodes for Neural Interfacing.

Neural interfacing devices using penetrating microelectrode arrays have emerged as an important tool in both neuroscience research and medical applications. These implantable microelectrode arrays enable communication between man-made devices and the nervous system by detecting and/or evoking neuronal activities. Recent years have seen rapid development of electrodes fabricated using flexible, ultrathin carbon-based microfibers. Compared to electrodes fabricated using rigid materials and larger cross-sections, these microfiber electrodes have been shown to reduce foreign body responses after implantation, with improved signal-to-noise ratio for neural recording and enhanced resolution for neural stimulation. Here, we review recent progress of carbon-based microfiber electrodes in terms of material composition and fabrication technology. The remaining challenges and future directions for development of these arrays will also be discussed. Overall, these microfiber electrodes are expected to improve the longevity and reliability of neural interfacing devices.

A 512-Channel Multi-Layer Polymer-Based Neural Probe Array.

We present for the first time the design, fabrication, and preliminary bench-top characterization of a high-density, polymer-based penetrating microelectrode array, developed for chronic, large-scale recording in the cortices and hippocampi of behaving rats. We present two architectures for these targeted brain regions, both featuring 512 Pt recording electrodes patterned front-and-back on micromachined eight-shank arrays of thin-film Parylene C. These devices represent an order of magnitude improvement in both number and density of recording electrodes compared with prior work on polymer-based microelectrode arrays. We present enabling advances in polymer micro-machining related to lithographic resolution and a new method for back-side patterning of electrodes. In vitro electrochemical data verifies suitable electrode function and surface properties. Finally, we describe next steps toward the implementation of these arrays in chronic, large-scale recording studies in free-moving animal models.

Hindlimb motor responses evoked by microstimulation of the lumbar dorsal root ganglia during quiet standing

Somatosensory afferent pathways have been a target for neural prostheses that seek to restore sensory feedback from amputated limbs and to recruit muscles paralyzed by neurological injury. These pathways supply inputs to spinal reflex circuits that are necessary for coordinating muscle activity in the lower limb. The dorsal root ganglia (DRG) is a potential site for accessing sensory neurons because DRG microstimulation selectively recruits major nerve branches of the cat hindlimb. Previous DRG microstimulation experiments have been performed in anesthetized animals, but effects on muscle recruitment and behavior in awake animals have not been examined. Objective. The objective of the current study was to measure the effects of DRG microstimulation on evoking changes in hindlimb muscle activity during quiet standing. Approach. In this study, 32-channel penetrating microelectrode arrays were implanted chronically in the left L6 and L7 DRG of four cats. During each week of testing, one DRG electrode was selected to deliver microstimulation pulse-trains during quiet standing. Electromyographic (EMG) signals were recorded from intramuscular electrodes in ten hindlimb muscles, and ground-reaction forces (GRF) were measured under the foot of the implanted limb. Main results. DRG Microstimulation evoked a mix of excitatory and inhibitory responses across muscles. Response rates were highest when microstimulation was applied on the L7 array, producing more excitatory than inhibitory responses. Response rates for the L6 array were lower, and the composition of responses was more evenly balanced between excitation and inhibition. On approximately one third of testing weeks, microstimulation induced a transient unloading of the hindlimb as indicated by a decrease in GRF. Reciprocal inhibition at the knee was a prevalent response pattern across testing days which contributed to the unloading force on this subset of testing weeks. Significance. Results show that single-channel microstimulation in the lumbar DRG evokes stereotyped patterns of muscle recruitment in awake animals, demonstrating that even limited sensory input can elicit hindlimb behavior. These findings imply that DRG microstimulation may have utility in neural prosthetic applications aimed at restoring somatosensory feedback and promoting motor function after neurological injury.

Selectivity of afferent microstimulation at the DRG using epineural and penetrating electrode arrays

Objective. We have shown previously that microstimulation of the lumbar dorsal root ganglia (L5-L7 DRG) using penetrating microelectrodes, selectively recruits distal branches of the sciatic and femoral nerves in an acute preparation. However, a variety of challenges limit the clinical translatability of DRG microstimulation via penetrating electrodes. For clinical translation of a DRG somatosensory neural interface, electrodes placed on the epineural surface of the DRG may be a viable path forward. The goal of this study was to evaluate the recruitment properties of epineural electrodes and compare their performance with that of penetrating electrodes. Here, we compare the number of selectively recruited distal nerve branches and the threshold stimulus intensities between penetrating and epineural electrode arrays. Approach. Antidromically propagating action potentials were recorded from multiple distal branches of the femoral and sciatic nerves in response to epineural stimulation on 11 ganglia in four cats to quantify the selectivity of DRG stimulation. Compound action potentials (CAPs) were recorded using nerve cuff electrodes implanted around up to nine distal branches of the femoral and sciatic nerve trunks. We also tested stimulation selectivity with penetrating microelectrode arrays implanted into ten ganglia in four cats. A binary search was carried out to identify the minimum stimulus intensity that evoked a response at any of the distal cuffs, as well as whether the threshold response selectively occurred in only a single distal nerve branch. Main results. Stimulation evoked activity in just a single peripheral nerve through 67% of epineural electrodes (35/52) and through 79% of the penetrating microelectrodes (240/308). The recruitment threshold (median = 9.67 nC/phase) and dynamic range of epineural stimulation (median = 1.01 nC/phase) were significantly higher than penetrating stimulation (0.90 nC/phase and 0.36 nC/phase, respectively). However, the pattern of peripheral nerves recruited for each DRG were similar for stimulation through epineural and penetrating electrodes. Significance. Despite higher recruitment thresholds, epineural stimulation provides comparable selectivity and superior dynamic range to penetrating electrodes. These results suggest that it may be possible to achieve a highly selective neural interface with the DRG without penetrating the epineurium.

The Reconnecting the Hand and Arm with Brain (ReHAB) Commentary on "An Integrated Brain-Machine Interface Platform With Thousands of Channels".

Intracortical brain-machine interfaces are a promising technology for allowing people with chronic and severe neurological disorders that resulted in loss of function to potentially regain those functions through neuroprosthetic devices. The penetrating microelectrode arrays used in almost all previous studies of intracortical brain-machine interfaces in people had a limited recording life (potentially due to issues with long-term biocompatibility), as well as a limited number of recording electrodes with limited distribution in the brain. Significant advances are required in this array interface to deal with the issues of long-term biocompatibility and lack of distributed recordings. The Musk and Neuralink manuscript proposes a novel and potentially disruptive approach to advancing the brain-electrode interface technology, with the potential of addressing many of these hurdles. Our commentary addresses the potential advantages of the proposed approach, as well as the remaining challenges to be addressed.

An Intrafascicular Neural Interface With Enhanced Interconnection for Recording of Peripheral Nerve Signals.

For implantable devices, Parylene C (hereafter referred to as Parylene) has shown promising properties such as flexibility, biocompatibility, biostability, and good barrier properties. Parylene-based flexible interconnection cable (FIC) was previously developed to connect a flexible penetrating microelectrode array (FPMA) with a recording system. However, Parylene-based FIC was difficult to handle and prone to damage during the implantation surgery because of its low mechanical strength. To improve the mechanical properties of the FIC, we suggest a mechanically enhanced flexible interconnection cable (enhanced FIC) obtained using a combination of Parylene and polyimide. To investigate the long-term stability of the enhanced FIC, Parylene-only FIC, and enhanced FIC were tested and their mechanical properties were compared under an accelerated aging condition. During the course of six months of soaking, the maximum strength of the enhanced FIC remained twice as high as that of the Parylene-only FIC throughout the experiment, although the mechanical strength of both FICs decreased over time. To show the capability of the enhanced FIC in the context of nerve signal recording as a part of a neural interfacing device, it was assembled together with the FPMA and custom-made wireless recording electronics. We demonstrated the feasibility of the enhanced FIC in an in vivo application by recording acute nerve signals from canine sciatic nerves.

Toward a Bidirectional Communication Between Retinal Cells and a Prosthetic Device - A Proof of Concept.

Background: Significant progress toward the recovery of useful vision in blind patients with severe degenerative retinal diseases caused by photoreceptor death has been achieved with the development of visual prostheses that stimulate the retina electrically. However, currently used prostheses do not provide feedback about the retinal activity before and upon stimulation and do not adjust to changes during the remodeling processes in the retina. Both features are desirable to improve the efficiency of the electrical stimulation (ES) therapy offered by these devices. Accordingly, devices that not only enable ES but at the same time provide information about the retinal activity are beneficial. Given the above, a bidirectional communication strategy, in which inner retinal cells are stimulated and the output neurons of the retina, the ganglion cells, are recorded using penetrating microelectrode arrays (MEAs) is proposed.Methods: Custom-made penetrating MEAs with four silicon-based shanks, each one with three or four iridium oxide electrodes specifically designed to match retinal dimensions were used to record the activity of light-adapted wildtype mice retinas and degenerated retinas from rd10 mice in vitro. In addition, responses to high potassium concentration and to light stimulation in wildtype retinas were examined. Furthermore, voltage-controlled ES was performed.Results: The spiking activity of retinal ganglion cells (RGCs) was recorded at different depths of penetration inside the retina. Physiological responses during an increase of the extracellular potassium concentration and phasic and tonic responses during light stimulation were captured. Moreover, pathologic rhythmic activity was recorded from degenerated retinas. Finally, ES of the inner retina and simultaneous recording of the activity of RGCs was accomplished.Conclusion: The access to different layers of the retina with penetrating electrodes while recording at the same time the spiking activity of RGCs broadens the use and the field of action of multi-shank and multi-site penetrating MEAs for retinal applications. It enables a bidirectional strategy to stimulate inner retinal cells electrically and to record from the spiking RGCs simultaneously (BiMEA). This opens the possibility of a feedback loop system to acknowledge the success of ES carried out by retinal prostheses.

Transparent, Flexible, Penetrating Microelectrode Arrays with Capabilities of Single-Unit Electrophysiology.

Accurately mapping neuronal activity across brain networks is critical to understand behaviors, yet it is very challenging due to the need of tools with both high spatial and temporal resolutions. Here, penetrating arrays of flexible microelectrodes made of low-impedance nanomeshes are presented, which are capable of recording single-unit electrophysiological neuronal activity and at the same time, transparent, allowing to bridge electrical and optical brain mapping modalities. These 32 transparent penetrating electrodes with site area, 225 µm2 , have a low impedance of ≈149 kΩ at 1 kHz, an adequate charge injection limit of ≈0.76 mC cm-2 , and up to 100% yield. Mechanical bending tests reveal that the array is robust up to 1000 bending cycles, and its high transmittance of 67% at 550 nm makes it suitable for combining with various optical methods. A temporary stiffening using polyethylene glycol allows the penetrating nanomesh arrays to be inserted into the brain minimally invasively, with in vivo validation of recordings of spontaneous and evoked single-unit activity of neurons across layers of the mouse visual cortex. Together, these results establish a novel neurotechnology-transparent, flexible, penetrating microelectrode arrays-which possesses great potential for brain research.

Correction to: Polymer-based interconnection cables to integrate with flexible penetrating microelectrode arrays.

The original version of this article unfortunately contained a mistake. In Eqs. (1) to (3), the gas constant 'R' should be replaced with Boltzmann constant 'k B.' This change accompanies the change in the paragraph following Eq. (3) as below.

Selective recurrent laryngeal nerve stimulation using a penetrating electrode array in the feline model.

Laryngeal muscles (LMs) are controlled by the recurrent laryngeal nerve (RLN), injury of which can result in vocal fold (VF) paralysis (VFP). We aimed to introduce a bioelectric approach to selective stimulation of LMs and graded muscle contraction responses. Acute experiments in cats. The study included six anesthetized cats. In four cats, a multichannel penetrating microelectrode array (MEA) was placed into an uninjured RLN. For RLN injury experiments, one cat received a standardized hemostat-crush injury, and one cat received a transection-reapproximation injury 4 months prior to testing. In each experiment, three LMs (thyroarytenoid, posterior cricoarytenoid, and cricothyroid muscles) were monitored with an electromyographic (EMG) nerve integrity monitoring system. Electrical current pulses were delivered to each stimulating channel individually. Elicited EMG voltage outputs were recorded for each muscle. Direct videolaryngoscopy was performed for visualization of VF movement. Stimulation through individual channels led to selective activation of restricted nerve populations, resulting in selective contraction of individual LMs. Increasing current levels resulted in rising EMG voltage responses. Typically, activation of individual muscles was successfully achieved via single placement of the MEA by selection of appropriate stimulation channels. VF abduction was predominantly observed on videolaryngoscopy. Nerve histology confirmed injury in cases of RLN crush and transection experiments. We demonstrated the ability of a penetrating MEA to selectively stimulate restricted fiber populations within the feline RLN and selectively elicit contractions of discrete LMs in both acute and injury-model experiments, suggesting a potential role for intraneural MEA implantation in VFP management. NA. Laryngoscope, 128:1606-1614, 2018.

An astrocyte derived extracellular matrix coating reduces astrogliosis surrounding chronically implanted microelectrode arrays in rat cortex

Available evidence suggests that the magnitude of the foreign body response (FBR) to implants placed in cortical brain tissue is affected by the extent of vasculature damage following device insertion and the magnitude of the ensuing macrophage response. Since the extracellular matrix (ECM) serves as a natural hemostatic and immunomodulatory agent, we examined the ability of an FDA-approved neurosurgical hemostatic coating and an ECM coating derived from primary rat astrocytes to reduce the FBR surrounding a penetrating microelectrode array chronically implanted in rat cortex. Using quantitative methods, we examined various components of the FBR in vitro and after implantation. In vitro assays showed that both coatings accelerated coagulation in a similar fashion but only the astrocyte-derived material suppressed macrophage activation. In addition, the ECM coating derived from astrocytes, also decreased the astrogliotic response 8 weeks after implantation. Neither coating had a significant influence on the intensity or spatial distribution of FBR biomarkers 1 week after implantation or on degree of macrophage activation or neuronal survival at the later time point. The results show that microelectrode coatings with similar hemostatic properties but different immunomodulatory characteristics differentially affect the FBR to an anchored, single-shank, silicon microelectrode array. The results also support the concept that divergent biological pathways affect the various components of the FBR in the CNS and suggests that decreasing its impact will require a multifaceted approach.

(Invited) Multimodal Microelectrode Failure Analysis Reveals Complex Relationship at the Neural Interface

Penetrating microelectrode arrays that can record extracellular action potentials from small, targeted groups of neurons are critical for basic neuroscience research and emerging clinical applications. However, these electrode devices suffer from reliability and variability issues which impact their performance on the order of months to years. The failure mechanisms of these electrodes are understood to be a complex combination of the biotic and abiotic failure modes. The breaching of the blood–brain barrier (BBB) to insert devices triggers a cascade of biochemical pathways resulting in complex molecular and cellular responses to implanted devices. Molecular and cellular changes in the microenvironment surrounding an implant include the introduction of mechanical strain, BBB leakage, activation of glial cells, loss of perfusion, secondary metabolic injury, and neuronal degeneration. The resulting inflammation is a key hypothesized cause of neural recording failure. However, previous attempt so directly correlate recording performance, to impedance, and to histological outcomes have led counter-intuitive and sometimes conflicting outcomes. One reason is that many neurons remain quiescent during anesthetized or resting-state conditions. We previously demonstrated this by visually evoked stimulation paradigms of the contralateral eye in order to evaluate chronic recording performance of linear silicon electrode in the primary visual cortex. Additional, multiphoton analysis using GCaMP6 transgenic animals further confirmed these results. More recently, there has been a growing interesting recording during awake free-roaming conditions in the primary motor cortex in order to avoid resting-state related quiescent activity. However, this in turn leads to increases in Lenz’s Law related artefacts that have the same time constants and waveform shapes as action potentials in rodents, but not NHP. While behaviorally training animals to remain immobile could improve outcomes, it also introduces the potential for Experimenter Expectancy Effect bias on the outcomes. The visual stimulation paradigm enable the use of current source density analysis to electrophysiologically identify Layer II/III, IV, and V in the cortex. This, in turn, allowed correlation of electrophysiological layers to the histological layers based on section depth and the differences in neural morphology and density. Our findings from electrophysiology, impedance spectroscopy, and post-mortem histology demonstrate a very poor relationship between histology and impedance to electrophysiology. For example, tissue with low-levels of glial encapsulation, healthy neuronal proximity, and low impedance can still have poor recording performance, even with neural activity is behaviorally driven. Even when histology confirms a perfect tissue interface, cracking or delamination of insulation on the microelectrode has been linked to a drop in impedance and a loss of recording failure. In contrast, cracking of the electrical trace and delamination of the recording site has been linked to recording failure through a jump in electrical impedance. As such, several modes of mechanical failure of chronically implanted planar silicon electrodes were found that result in degradation and/or loss of recording. Our findings highlight the importance of strains and material properties of various subcomponents within an electrode array and the poor reliability of determining electrode viability through electrochemical impedance spectroscopy. Interestingly, we discovered in a number of situations that even with good neural density, uncompromised electrode material, and good impedances, recording performance can sometimes completely degrade. New multimodal analysis demonstrates the importance of capturing dynamic information, such as with in vivo multiphoton study, and that the presence of neurons does not guarantee functional neural activity over time. We further demonstrate that the foundation of assumptions and simplification made in the field for neural interface research are not true or incomplete. To solve the longstanding chronic neural interface problem, we need to first understand the complexity of the problem.