Keith Mathieson

Cochlear and auditory brainstem implants are the primary treatments for profound deafness ¹ . However, the inherently low resolution of electrical stimulation used by these devices limits information transfer to a small number of independent stimulation channels ² and results in perceptual difficulties. An alternative approach is to target the auditory cortex, a brain region large enough to accommodate hundreds of stimulation channels and whose stimulation evokes sound percepts ^3,4 . Although modern brain interfaces offer large channel counts and spatial resolution, developing encoding algorithms capable of accurately transmitting interpretable sound information remains challenging. Here we introduce Braincodec, a deep network that optimizes both sound information transmission and the alignment of stimulation patterns with the spatial, temporal, and high-level properties of the auditory cortex neural code. Braincodec operates online and requires only a few hundred channels to transmit sufficient information for the reconstruction of natural sounds with high fidelity, a performance inaccessible to cochlear implant encoders. Moreover, mice equipped with a Braincodec-driven auditory cortical prosthesis matched the accuracy of non-implanted mice in discriminating real sounds. Braincodec therefore enables the development of high-throughput cortical neuroprosthetics with the potential to overcome the limitations of current auditory implants and provides a generic framework applicable to other sensory modalities.

Photovoltaic subretinal prosthesis, PRIMA, provides central vision to patients blinded by age-related macular degeneration, with acuity matching the 100 μm pixel size. Further miniaturization requires pillar electrodes to position the stimulating surfaces closer to the inner retinal neurons. While such structures can be electroplated in gold and coated on their tops with SIROF, the exposed gold sidewalls are not biocompatible. Sputtering or atomic layer deposition of protective coatings are unsuitable for selectively passivating the pillar structures without also coating the photosensitive regions and return electrodes of the implant. Here, we present a strategy for biocompatible coating of pillar sidewalls while preserving surrounding implant functionality. The approach combines non-critical photoresist lithography to protect planar return electrodes with electrodeposition of TiO2; or Pt onto gold pillar sidewalls. In-vivo studies demonstrated that both TiO2 and Pt coatings are biocompatible and prevent adverse reactions of the retinal tissue to gold. Since specific capacitance of electroplated TiO2 (25 μF/cm2) is much lower than that of Pt (240 μF/cm2), the former better limits the current from the side walls and ensures that charge injection occurs predominantly through the pillar tops coated with SIROF (~6 mF/cm2). Electrodeposition, combined with noncritical photolithography provides a scalable wafer-level solution for fabrication of biocompatible three-dimensional electro-neural interfaces, addressing a critical bottleneck in bioelectronics.

Cortical implants are a proven clinical neurotechnology with the potential to transform our understanding of cognitive processes. These processes rely on complex neuronal networks that are difficult to selectively probe or stimulate. Optogenetics offers cell-type specificity, but achieving the density and coverage required for chronic, high-resolution modulation remains a challenge. We fabricated 100-element μ LED arrays (200 μ m pixel pitch, 2 × 2 mm ² footprint) coupled into chronically implantable systems for optogenetic stimulation of the mouse cortex. The μ LEDs remain stable for over 300 hours continuous operation time in vivo, allowing for months-long chronic experiments. Simultaneous electrophysiology recordings confirmed robust neuronal responses at low μ LED drive currents (< 5 mA), minimising thermal effects. Here we show that our device can be chronically implanted in freely-behaving mice and drive behavioural outcomes from spatiotemporal, patterned, optogenetic stimulation of auditory cortical circuits.

Objective. Clinical trials of the photovoltaic subretinal prosthesis PRIMA demonstrated feasibility of prosthetic central vision with resolution matching its 100 µm pixel width. To improve prosthetic acuity further, pixel size should be decreased. However, there are multiple challenges, one of which is related to accommodating a compact shunt resistor within each pixel that discharges the electrodes between stimulation pulses and helps increase the contrast of the electric field pattern. Unfortunately, standard materials used in integrated circuit resistors do not match the resistivity required for small photovoltaic pixels. Therefore, we used a novel material—doped amorphous silicon (a-Si) and integrated it into photovoltaic arrays with pixel sizes down to 20 µm. Approach. To fit within a few µm² area of the pixels and provide resistance in the MΩ range, the material should have sheet resistance of a few 100 kΩ sq⁻¹, which translates to resistivity of a few Ω * cm. The a-Si layer was deposited by low-pressure chemical vapor deposition and its resistivity was adjusted by PH₃ doping before encapsulating the resistors between SiO₂ and SiC for stability in-vivo. Main results. High-resolution retinal implants with integrated shunt resistors were fabricated with values ranging from 0.75 to 4 MΩ on top of the photovoltaic pixels of 55, 40, 30 and 20 µm in size. Photoresponsivity with all pixel sizes was approximately 0.53 A W⁻¹, as high as in the arrays with no shunt resistor. The shunts shortened electrodes discharge time, with the average electric potential in electrolyte decreasing by only 21%–31 % when repetition rate increased from 2 to 30 Hz, as opposed to a 54%–55 % decrease without a shunt. Similarly, contrast of a Landolt C pattern increased from 16%–22 % with no shunt to 22%–34 % with a shunt. Further improvement in contrast is expected with pillar electrodes and local returns within each pixel. Significance. Miniature shunt resistors in a MΩ range can be fabricated from doped a-Si in a process compatible with manufacturing of photovoltaic arrays. The shunt resistors improved current injection and spatial contrast at video frame rates, without compromising the photoresponsivity. These advances are critical for scaling pixel sizes below 100 µm to improve visual acuity of prosthetic vision.

SignificanceCurrent preclinical evaluation of Alzheimer’s disease pathology in mouse models relies on post-mortem analyses, which hinders the development and optimization of therapeutic approaches. Although in vivo methods exist, monitoring amyloid plaque signals across multiple brain regions in freely behaving animals remains a significant challenge.AimWe aim to develop an optical approach to address this challenge.ApproachWe used flat and tapered optical fibers in an Alzheimer’s mouse model.ResultsWe first confirmed that conventional flat fiber-based photometry can detect amyloid plaque signals across multiple brain regions under anesthesia after injecting a blood-brain-barrier-permeable tracer, Methoxy-X04. The depth profile of in vivo fluorescent signals is correlated with histological signals. A machine learning approach could distinguish between in vivo fluorescent signals of mice with and without amyloid plaques. Next, after validating the feasibility of depth-resolved fiber photometry ex vivo, we chronically implanted a tapered fiber to monitor amyloid plaque signals in freely behaving mice. After injecting Methoxy-X04, fluorescent signals increased in a depth-specific manner in Alzheimer’s mice, but not in their wild-type littermates.ConclusionsOur approach expands the capabilities of fiber photometry to monitor molecular pathologies, such as amyloid plaques, even in a freely behaving condition.

Objective: Clinical trials of the photovoltaic subretinal prosthesis PRIMA demonstrated feasibility of prosthetic central vision with resolution matching its 100µm pixel size. To improve prosthetic acuity further, pixel size should be decreased. However, there are multiple challenges, one of which is related to accommodating a compact shunt resistor within each pixel that discharges the electrodes between stimulation pulses and helps increase the contrast of the electric field pattern. Unfortunately, standard materials used in integrated circuit resistors do not match the resistivity required for small photovoltaic pixels. Therefore, we used a novel material – doped amorphous silicon (a-Si) and integrated it into photovoltaic arrays with pixel sizes down to 20µm. Approach: To fit within a few µm ² area of the pixels and provide resistance in the MΩ range, the material should have sheet resistance of a few hundred kΩ/sq, which translates to resistivity of a few Ω*cm. The a-Si layer was deposited by low-pressure chemical vapor deposition (LPCVD) and its resistivity was adjusted by PH ₃ doping before encapsulating the resistors between SiO ₂ and SiC for stability in-vivo. Main Results: High-resolution retinal implants with integrated shunt resistors were fabricated with values ranging from 0.75 to 4 MΩ on top of the photovoltaic pixels of 55, 40, 30 and 20 µm in size. Photoresponsivity with all pixel sizes was approximately 0.53 A/W, as high as in the arrays with no shunt resistor. The shunts shortened electrodes discharge time, with the average electric potential in electrolyte decreasing by only 21–31% when repetition rate increased from 2 to 30 Hz, as opposed to a 54–55% decrease without a shunt. Similarly, contrast of a Landolt C pattern increased from 16-22% with no shunt to 22–34% with a shunt. Further improvement in contrast is expected with pillar electrodes and local returns within each pixel. Significance: Miniature shunt resistors in a MOhm range can be fabricated from doped a-Si in a process compatible with manufacturing of photovoltaic arrays. The shunt resistors improved current injection and spatial contrast at video frame rates, without compromising the photoresponsivity. These advances are critical for scaling pixel sizes below 100 µm to improve visual acuity of prosthetic vision.

In patients with atrophic age-related macular degeneration, subretinal photovoltaic implant (PRIMA) provided visual acuity up to 20/440, matching its 100 µm pixels size. Next-generation implants with smaller pixels should significantly improve the acuity. This study in rats evaluates removal of a subretinal implant, replacement with a newer device, and the resulting grating acuity in-vivo. Six weeks after the initial implantation with planar and 3-dimensional devices, the retina was re-detached, and the devices were successfully removed. Histology demonstrated a preserved inner nuclear layer. Re-implantation of new devices into the same location demonstrated retinal re-attachment to a new implant. New devices with 22 µm pixels increased the grating acuity from the 100 µm capability of PRIMA implants to 28 µm, reaching the limit of natural resolution in rats. Reimplanted devices exhibited the same stimulation threshold as for the first implantation of the same implants in a control group. This study demonstrates the feasibility of safely upgrading the subretinal photovoltaic implants to improve prosthetic visual acuity.

Cortical implants are a proven clinical neurotechnology with the potential to transform our understanding of cognitive processes. These processes rely on complex neuronal networks that are difficult to selectively probe or stimulate. Optogenetics offers cell-type specificity, but achieving the density and coverage required for chronic, high-resolution modulation remains a challenge. Here we present a 100-element µLED array (200 µm pixel pitch, 2 × 2 mm2 footprint) coupled into a miniaturised, flexible system suitable for chronic implantation and optogenetic stimulation of the surface of the mouse cortex. The µLEDs can remain stable for over 300 hours continuous operation time in-vivo , allowing for months-long chronic experiments. Simultaneous electrophysiology recordings confirmed robust neuronal responses corresponding to low µLED drive currents (<5 mA), minimising thermal effects and supporting future wireless operation. The spatial resolution of neuronal responses was consistent with a simulated model of light scattering in the cortical layers, enabling device optimisation. Behavioural experiments with chronically implanted mice demonstrated robust learning during discrimination tasks using spatially distinct optogenetic stimulation patterns.

Objective. Optogenetics allows the manipulation of neural circuits in vivo with 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 tested in vivo, the Utah Optrode Array (UOA), an electrically addressable array of optical needles and interstitial sites illuminated by 181 μLEDs and used to optogenetically stimulate the brain. The device is specifically designed for non-human primate studies. Main results. Thinning the combined μLED and needle backplane of the device from 300 μm to 230 μm improved the efficiency of light delivery to tissue by 80%, allowing lower μLED 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 tested in vivo in 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.

Optogenetics allows manipulation of neural circuits in vivo with 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). Here, we have developed, optimised, and tested in vivo, the Utah Optrode Array (UOA), an electrically addressable array of optical needles and interstitial sites illuminated by 181 µLEDs and used to optogenetically stimulate the brain. The device is specifically designed for non-human primate studies. Thinning the combined µLED and needle backplane of the device from 300 µm to 230 µm improved the efficiency of light delivery to tissue by 80%, allowing lower µLED 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 tested in vivo in the visual cortex of macaque expressing ChR2-tdTomato in cortical neurons. It was shown that the strongest optogenetic response occurred 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 (LFP) activity.