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Abstract Optogenetics has transformed studies of neural circuit function, but remains challenging to apply to non-human primates (NHPs). A major challenge is delivering intense, spatiotemporally-precise, patterned photostimulation across large volumes in deep tissue. Such stimulation is critical, for example, to modulate selectively deep-layer corticocortical feedback circuits. To address this need, we have developed the Utah Optrode Array (UOA), a 10×10 glass needle waveguide array fabricated atop a novel opaque optical interposer, and bonded to an electrically addressable µLED array. In vivo experiments with the UOA demonstrated large-scale, spatiotemporally precise, activation of deep circuits in NHP cortex. Specifically, the UOA permitted both focal (confined to single layers/columns), and widespread (multiple layers/columns) optogenetic activation of deep layer neurons, as assessed with multi-channel laminar electrode arrays, simply by varying the number of activated µLEDs and/or the irradiance. Thus, the UOA represents a powerful optoelectronic device for targeted manipulation of deep-layer circuits in NHP models.
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Cortical Response to Acute Implantation of the Utah Optrode Array in Macaque Cortex
ABSTRACT Optogenetics has transformed the study of neural circuit function, but limitations in its application to species with large brains, such as non-human primates (NHPs), remain. A major challenge in NHP optogenetics is delivering light to sufficiently large volumes of deep neural tissue with high spatiotemporal precision, without simultaneously affecting superficial tissue. To overcome these limitations, we recently developed and testedin vivoin NHP cortex, the Utah Optrode Array (UOA). This is a 10×10 array of penetrating glass shanks, tiling a 4×4mm2area, bonded to interleaved needle-aligned and interstitial µLED arrays, which allows for independent photostimulation of deep and superficial brain tissue. Here, we investigate the acute biological response to UOA implantation in NHP cortex, with the goal of optimizing device design for reduced insertion trauma and subsequent chronic response. To this goal, we systematically vary UOA shank diameter, surface texture, tip geometry, and insertion pressure, and assess their effects on astrocytes, microglia, and neuronal viability, following acute implantation. We find that UOAs with shanks of smaller diameter, smooth surface texture and round tips cause the least damage. Higher insertion pressures have limited effects on the inflammatory response, but lead to greater tissue compression. Our results highlight the importance of balancing shank diameter, tip geometry, and insertion pressure in UOA design for preserving tissue integrity and improving long-term UOA performance and biocompatibility.
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- Award ID(s):
- 1755431
- PAR ID:
- 10571309
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- University of Utah
- Sponsoring Org:
- National Science Foundation
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Optogenetics has transformed studies of neural circuit function, but remains challenging to apply in non-human primates (NHPs). A major challenge is delivering intense and spatially precise patterned photostimulation across large volumes in deep tissue. Here, we have developed and tested the Utah Optrode Array (UOA) to meet this critical need. The UOA is a 10×10 glass waveguide array bonded to an electrically-addressable μLED array. In vivo electrophysiology and immediate early gene (c-fos) immunohistochemistry demonstrate that the UOA allows for large-scale spatiotemporally precise neuromodulation of deep tissue in macaque primary visual cortex. Specifically, the UOA permits either focal (confined to single layers or columns), or large-scale (across multiple layers or columns) photostimulation of deep cortical layers, simply by varying the number of simultaneously activated μLEDs and/or the light irradiance. These results establish the UOA as a powerful tool for studying targeted neural populations within single or across multiple deep layers in complex NHP circuits.more » « less
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Abstract Objective. The Utah array is widely used in both clinical studies and neuroscience. It has a strong track record of safety. However, it is also known that implanted electrodes promote the formation of scar tissue in the immediate vicinity of the electrodes, which may negatively impact the ability to record neural waveforms. This scarring response has been primarily studied in rodents, which may have a very different response than primate brain. Approach. Here, we present a rare nonhuman primate histological dataset ( n = 1 rhesus macaque) obtained 848 and 590 d after implantation in two brain hemispheres. For 2 of 4 arrays that remained within the cortex, NeuN was used to stain for neuron somata at three different depths along the shanks. Images were filtered and denoised, with neurons then counted in the vicinity of the arrays as well as a nearby section of control tissue. Additionally, 3 of 4 arrays were imaged with a scanning electrode microscope to evaluate any materials damage that might be present. Main results. Overall, we found a 63% percent reduction in the number of neurons surrounding the electrode shanks compared to control areas. In terms of materials, the arrays remained largely intact with metal and Parylene C present, though tip breakage and cracks were observed on many electrodes. Significance. Overall, these results suggest that the tissue response in the nonhuman primate brain shows similar neuron loss to previous studies using rodents. Electrode improvements, for example using smaller or softer probes, may therefore substantially improve the tissue response and potentially improve the neuronal recording yield in primate cortex.more » « less
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Abstract Objective.Optogenetics allows the manipulation of neural circuitsin vivowith high spatial and temporal precision. However, combining this precision with control over a significant portion of the brain is technologically challenging (especially in larger animal models).Approach.Here, we have developed, optimised, and testedin vivo, the Utah Optrode Array (UOA), an electrically addressable array of optical needles and interstitial sites illuminated by 181μLEDs and used to optogenetically stimulate the brain. The device is specifically designed for non-human primate studies.Main results.Thinning the combinedμLED and needle backplane of the device from 300μm to 230μm improved the efficiency of light delivery to tissue by 80%, allowing lowerμLED drive currents, which improved power management and thermal performance. The spatial selectivity of each site was also improved by integrating an optical interposer to reduce stray light emission. These improvements were achieved using an innovative fabrication method to create an anodically bonded glass/silicon substrate with through-silicon vias etched, forming an optical interposer. Optical modelling was used to demonstrate that the tip structure of the device had a major influence on the illumination pattern. The thermal performance was evaluated through a combination of modelling and experiment, in order to ensure that cortical tissue temperatures did not rise by more than 1 °C. The device was testedin vivoin the visual cortex of macaque expressing ChR2-tdTomato in cortical neurons.Significance.It was shown that the UOA produced the strongest optogenetic response in the region surrounding the needle tips, and that the extent of the optogenetic response matched the predicted illumination profile based on optical modelling—demonstrating the improved spatial selectivity resulting from the optical interposer approach. Furthermore, different needle illumination sites generated different patterns of low-frequency potential activity.more » « less
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Abstract Objective. The insertion of penetrating neural probes into the brain is crucial for advancing neuroscience, yet it involves various inherent risks. Prototype probes are typically inserted into hydrogel-based brain phantoms and the mechanical responses are analyzed in order to inform the insertion mechanics duringin vivoimplantation. However, the underlying mechanism of the insertion dynamics of neural probes in hydrogel brain phantoms, particularly the phenomenon of cracking, remains insufficiently understood. This knowledge gap leads to misinterpretations and discrepancies when comparing results obtained from phantom studies to those observed under thein vivoconditions. This study aims to elucidate the impact of probe sharpness and dimensions on the cracking mechanisms and insertion dynamics characterized during the insertion of probes in hydrogel phantoms.Approach. The insertion of dummy probes with different shank shapes defined by the tip angle, width, and thickness is systematically studied. The insertion-induced cracks in the transparent hydrogel were accentuated by an immiscible dye, tracked byin situimaging, and the corresponding insertion force was recorded. Three-dimensional finite element analysis models were developed to obtain the contact stress between the probe tip and the phantom.Main results. The findings reveal a dual pattern: for sharp, slender probes, the insertion forces remain consistently low during the insertion process, owing to continuously propagating straight cracks that align with the insertion direction. In contrast, blunt, thick probes induce large forces that increase rapidly with escalating insertion depth, mainly due to the formation of branched crack with a conical cracking surface, and the subsequent internal compression. This interpretation challenges the traditional understanding that neglects the difference in the cracking modes and regards increased frictional force as the sole factor contributing to higher insertion forces. The critical probe sharpness factors separating straight and branched cracking is identified experimentally, and a preliminary explanation of the transition between the two cracking modes is derived from three-dimensional finite element analysis.Significance. This study presents, for the first time, the mechanism underlying two distinct cracking modes during the insertion of neural probes into hydrogel brain phantoms. The correlations between the cracking modes and the insertion force dynamics, as well as the effects of the probe sharpness were established, offering insights into the design of neural probes via phantom studies and informing future investigations into cracking phenomena in brain tissue during probe implantations.more » « less
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Accepted Manuscript1.0
- Posted Content:
- https://doi.org/10.1101/2025.01.13.632843
