A novel microwire interface for small diameter peripheral nerves in a chronic, awake murine model.

OBJECTIVE: The vagus nerve has been implicated in a variety of immune responses, and the number of studies using mouse models to unravel key mechanisms has increased. However, as of yet, there is no electrode that can chronically record neural activity from the mouse vagus nerve due to its small diameter. Such recordings are critical to understand the role of these biomarkers for translational research. APPROACH: In this study, we developed a methodology for surgically implanting the wrappable microwires onto the vagus nerve of mice. Similar to a cuff electrode, we wrapped de-insulated ends of microwires around the vagus nerve and re-insulated them on the nerve with Kwik-Sil. The recording fidelity of the wrappable microwire on the vagus nerve was validated in an acute, anesthetized model by comparing performance to commercially-available electrodes. A chronic, awake mouse model was then developed to record spontaneous compound action potentials (CAPs). MAIN RESULTS: In an acute setting, the wrappable microwire successfully recorded spontaneous CAPs with similar signal-to-noise ratios (SNR) and peak-to-peak amplitude to commercially available electrodes. In chronic, awake recordings, viable SNRs were obtained from the wrappable microwires between 30 and 60 d (n = 8). Weekly impedance measurements showed no correlation with SNR or time, indicating device stability, and the electrodes recorded CAPs for the duration of the recording period. SIGNIFICANCE: To the best of our knowledge, this is the first reported chronic, awake neural interface with the mouse vagus nerve. This approach can facilitate clinical translation for bioelectronic medicine in preclinical disease models of interest with the creation of more clinically relevant preclinical models.

The impact of modulating the blood-brain barrier on the electrophysiological and histological outcomes of intracortical electrodes.

OBJECTIVE: Successful application of chronic intracortical electrodes remains highly variable. The biological mechanisms leading to electrode failure are still being explored. Recent work has shown a correlation between blood-brain barrier (BBB) integrity and long-term recordings. Here we proposed to modulate the BBB healing after intracortical electrode implantation, while evaluating the functional electrophysiology. The CCL2/CCR2 pathway was chosen based on previous work demonstrating the positive histological effects in an intracortical electrode model, as well as in other neurodegenerative models. By disrupting this pathway, recruitment of pro-inflammatory monocytes (a result of a breached BBB) is potentially reduced at the electrode interface. APPROACH: Michigan electrodes were implanted for 2 and 12 weeks in rats, and a CCR2 antagonist (RS 102895) was administered daily to the treatment group. Functional electrodes were used for the 12 week cohort, and weekly electrophysiological recordings were taken. At 2 and 12 weeks, histology was analyzed. MAIN RESULTS: At 12 weeks, the CCR2-antagonist group had significantly higher signal-to-noise ratios (SNRs) than control. CCR2-antagonism at 2 weeks significantly increased the neural population and decreased BBB breach. At 12 weeks, CCR2-antagonism significantly increased number of neurons and BBB + vasculature within 100 µm of the electrode interface. SIGNIFICANCE: This work demonstrates that for intracortical electrodes, disruption of the CCL2/CCR2 pathway improves chronic outcomes in electrophysiology and histology.

Correlation of mRNA Expression and Signal Variability in Chronic Intracortical Electrodes.

OBJECTIVE: The goal for this research was to identify molecular mechanisms that explain animal-to-animal variability in chronic intracortical recordings. APPROACH: Microwire electrodes were implanted into Sprague Dawley rats at an acute (1 week) and a chronic (14 weeks) time point. Weekly recordings were conducted, and action potentials were evoked in the barrel cortex by deflecting the rat's whiskers. At 1 and 14 weeks, tissue was collected, and mRNA was extracted. mRNA expression was compared between 1 and 14 weeks using a high throughput multiplexed qRT-PCR. Pearson correlation coefficients were calculated between mRNA expression and signal-to-noise ratios at 14 weeks. MAIN RESULTS: At 14 weeks, a positive correlation between signal-to-noise ratio (SNR) and NeuN and GFAP mRNA expression was observed, indicating a relationship between recording strength and neuronal population, as well as reactive astrocyte activity. The inflammatory state around the electrode interface was evaluated using M1-like and M2-like markers. Expression for both M1-like and M2-like mRNA markers remained steady from 1 to 14 weeks. Anti-inflammatory markers, CD206 and CD163, however, demonstrated a significant positive correlation with SNR quality at 14 weeks. VE-cadherin, a marker for adherens junctions, and PDGFR-ß, a marker for pericytes, both partial representatives of blood-brain barrier health, had a positive correlation with SNR at 14 weeks. Endothelial adhesion markers revealed a significant increase in expression at 14 weeks, while CD45, a pan-leukocyte marker, significantly decreased at 14 weeks. No significant correlation was found for either the endothelial adhesion or pan-leukocyte markers. SIGNIFICANCE: A positive correlation between anti-inflammatory and blood-brain barrier health mRNA markers with electrophysiological efficacy of implanted intracortical electrodes has been demonstrated. These data reveal potential mechanisms for further evaluation to determine potential target mechanisms to improve consistency of intracortical electrodes recordings and reduce animal-to-animal/implant-to-implant variability.

A regenerative microchannel device for recording multiple single-unit action potentials in awake, ambulatory animals.

Despite significant advances in robotics, commercially advanced prosthetics provide only a small fraction of the functionality of the amputated limb that they are meant to replace. Peripheral nerve interfacing could provide a rich controlling link between the body and these advanced prosthetics in order to increase their overall utility. Here, we report on the development of a fully integrated regenerative microchannel interface with 30 microelectrodes and signal extraction capabilities enabling evaluation in an awake and ambulatory rat animal model. In vitro functional testing validated the capability of the microelectrodes to record neural signals similar in size and nature to those that occur in vivo. In vitro dorsal root ganglia cultures revealed striking cytocompatibility of the microchannel interface. Finally, in vivo, the microchannel interface was successfully used to record a multitude of single-unit action potentials through 63% of the integrated microelectrodes at the early time point of 3 weeks. This marks a significant advance in microchannel interfacing, demonstrating the capability of microchannels to be used for peripheral nerve interfacing.

Cochlear implantation using thin-film array electrodes.

OBJECTIVE: Current limitations in language perception may stem from an inability to provide high-resolution sound input. Thin-film array technology allows for a greater density of stimulating sites within the limited diameter of the scala tympani. This study examines the use of a flexible carrier to achieve adequate depth of insertion. STUDY DESIGN: A prospective human cadaveric temporal bone insertion analysis. SETTING: Academic otolaryngology department and school of electrical and computer engineering collaboration. METHODS: A prototype thin-film array electrode coupled with an insertion test device (ITD) was manufactured and inserted into 10 human cadaveric temporal bones. As controls, 2 additional temporal bones were implanted with the ITD only and 2 were unimplanted. Radiologic and histologic data were collected. RESULTS: Ten thin-film array electrodes were successfully implanted into 10 individual temporal bones via round window (5) and cochleostomy (5) approaches. Seventeen millimeters of insertion was noted for each device, with an average angular insertion depth of 292° by radiographic measurements and 392° by histologic sectioning. Electrode distance to the modiolus averaged 0.88 mm by computed tomography and 0.67 mm by histologic measurements. Average percentage trauma was 26% for the ITD-backed arrays compared with 15% and 29% for ITD only and unimplanted temporal bones, respectively. CONCLUSION: Thin-film array electrodes coupled with an ITD were successfully inserted into the human cochlea with limited trauma. With continued development and testing of this electrode design, the thin-film array may improve the language perception achieved through cochlear implantation.

Current steering and current focusing with a high-density intracochlear electrode array.

Creating high-resolution or high-density, intra-cochlear electrode arrays may significantly improve quality of hearing for cochlear implant recipients. Through focused activation of neural populations such arrays may better exploit the cochlea's frequency-to-place mapping, thereby improving sound perception. Contemporary electrode arrays approach high-density stimulation by employing multi-polar stimulation techniques such as current steering and current focusing. In our procedure we compared an advanced high-density array with contemporary arrays employing these strategies. We examined focused stimulation of auditory neurons using an activating function and a neural firing probability model that together enable a first-order estimation of an auditory nerve fiber's response to electrical stimulation. The results revealed that simple monopolar stimulation with a high-density array is more localized than current steering with a contemporary array and requires 25-30% less current. Current focusing with high-density electrodes is more localized than current focusing with a contemporary array; however, a greater amount of current is required. This work illustrates that advanced high-density electrode arrays may provide a low-power, high-resolution alternative to current steering with contemporary cochlear arrays.