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  1. Current standards for safe delivery of electrical stimulation to the central nervous system are based on foundational studies which examined post-mortem tissue for histological signs of damage. This set of observations and the subsequently proposed limits to safe stimulation, termed the “Shannon limits,” allow for a simple calculation (using charge per phase and charge density) to determine the intensity of electrical stimulation that can be delivered safely to brain tissue. In the three decades since the Shannon limits were reported, advances in molecular biology have allowed for more nuanced and detailed approaches to be used to expand current understanding of the physiological effects of stimulation. Here, we demonstrate the use of spatial transcriptomics (ST) in an exploratory investigation to assess the biological response to electrical stimulation in the brain. Electrical stimulation was delivered to the rat visual cortex with either acute or chronic electrode implantation procedures. To explore the influence of device type and stimulation parameters, we used carbon fiber ultramicroelectrode arrays (7 μm diameter) and microwire electrode arrays (50 μm diameter) delivering charge and charge density levels selected above and below reported tissue damage thresholds (range: 2–20 nC, 0.1–1 mC/cm 2 ). Spatial transcriptomics was performed using Visium Spatialmore »Gene Expression Slides (10x Genomics, Pleasanton, CA, United States), which enabled simultaneous immunohistochemistry and ST to directly compare traditional histological metrics to transcriptional profiles within each tissue sample. Our data give a first look at unique spatial patterns of gene expression that are related to cellular processes including inflammation, cell cycle progression, and neuronal plasticity. At the acute timepoint, an increase in inflammatory and plasticity related genes was observed surrounding a stimulating electrode compared to a craniotomy control. At the chronic timepoint, an increase in inflammatory and cell cycle progression related genes was observed both in the stimulating vs. non-stimulating microwire electrode comparison and in the stimulating microwire vs. carbon fiber comparison. Using the spatial aspect of this method as well as the within-sample link to traditional metrics of tissue damage, we demonstrate how these data may be analyzed and used to generate new hypotheses and inform safety standards for stimulation in cortex.« less
    Free, publicly-accessible full text available July 19, 2023
  2. Ultrasmall microelectrode arrays have the potential to improve the spatial resolution of microstimulation. Carbon fiber (CF) microelectrodes with cross-sections of less than 8 μm have been demonstrated to penetrate cortical tissue and evoke minimal scarring in chronic implant tests. In this study, we investigate the stability and performance of neural stimulation electrodes comprised of electrodeposited platinum-iridium (PtIr) on carbon fibers. We conducted pulse testing and characterized charge injection in vitro and recorded voltage transients in vitro and in vivo. Standard electrochemical measurements (impedance spectroscopy and cyclic voltammetry) and visual inspection (scanning electron microscopy) were used to assess changes due to pulsing. Similar to other studies, the application of pulses caused a decrease in impedance and a reduction in voltage transients, but analysis of the impedance data suggests that these changes are due to surface modification and not permanent changes to the electrode. Comparison of scanning electron microscope images before and after pulse testing confirmed electrode stability.