A CMOS-based microelectrode array (CMOSMEA) is presented, where a 10-nm-thick antiferroelectric ZrO2 layer is deposited in the post-CMOS process as functional electrode coating for 4225 recording sites and 1024 stimulation sites. Voltage noise measurements of the ZrO2 recording sites of the CMOS-MEA show reduced noise levels as compared to the same CMOS-MEA with uncoated TiN electrodes. Moreover, neural recordings of spontaneous activity of retinal ganglion cells reveal full functionality and biocompatibility of the insulating ZrO2 interface material. The stimulation current of the ZrO2 ferroelectric microelectrodes is investigated by applying triangular voltage signals to the stimulation sites of the CMOSMEA. Up to voltage amplitudes of 3.2 V, the stimulation current consists of displacement current only, electrochemical (Faradaic) DC currents are suppressed. For voltage amplitudes above similar to 2.2 V, we observe a voltage-dependent increase in the stimulation current which we attribute to the ferroelectric properties of the ZrO2 insulated microelectrodes. However, the enhancement of the charge injection capacity (CIC) of the insulated microelectrodes is below the full potential of antiferroelectric ZrO2 and requires further optimization. Nevertheless, our results demonstrate the potential of ferroelectric CMOS-MEAs for safe and efficient neural recording and stimulation.

Objective.Neuromodulation, particularly electrical stimulation, necessitates high spatial resolution to achieve artificial vision with high acuity. In epiretinal implants, this is hindered by the undesired activation of distal axons. Here, we investigate focal and axonal activation of retinal ganglion cells (RGCs) in epiretinal configuration for different sinusoidal stimulation frequencies.Approach.RGC responses to epiretinal sinusoidal stimulation at frequencies between 40 and 100 Hz were tested inex-vivophotoreceptor degenerated (rd10) isolated retinae. Experiments were conducted using a high-density CMOS-based microelectrode array, which allows to localize RGC cell bodies and axons at high spatial resolution.Main results.We report current and charge density thresholds for focal and distal axon activation at stimulation frequencies of 40, 60, 80, and 100 Hz for an electrode size with an effective area of 0.01 mm2. Activation of distal axons is avoided up to a stimulation amplitude of 0.23µA (corresponding to 17.3µC cm-2) at 40 Hz and up to a stimulation amplitude of 0.28µA (14.8µC cm-2) at 60 Hz. The threshold ratio between focal and axonal activation increases from 1.1 for 100 Hz up to 1.6 for 60 Hz, while at 40 Hz stimulation frequency, almost no axonal responses were detected in the tested intensity range. With the use of synaptic blockers, we demonstrate the underlying direct activation mechanism of the ganglion cells. Finally, using high-resolution electrical imaging and label-free electrophysiological axon tracking, we demonstrate the extent of activation in axon bundles.Significance.Our results can be exploited to define a spatially selective stimulation strategy avoiding axonal activation in future retinal implants, thereby solving one of the major limitations of artificial vision. The results may be extended to other fields of neuroprosthetics to achieve selective focal electrical stimulation.

A three-dimensional finite element method (FEM) simulation of a neuron (retinal ganglion cell) interfaced to a high-density CMOS-based microelectrode array (MEA) is performed and compared to recordings. The adopted multiscale simulation approach accurately reproduces the signals recorded by the patch clamp and the MEA sensors. The simulation leads us to identify bendings of the axon initial segment of a few neurons embedded in tissue, which are reported here for the first time.

A Multi-Electrode-Array (MEA) in a 180 nm CMOS technology is presented with 4225 recording sides, 4225 recording channels, and 1024 stimulation sites. The two versions of the chip provide active areas of 2.3 mm x 2.3 mm and 4.1 mm x 4.1 mm with a spacial recording site resolution of 36 µm and 64 µm, respectively. The devices are capable of full imaging at a frame rate of 25 kHz at an input-referred noise of 13.1 µVrms in the action potential (AP) band from 300 Hz to 10 kHz, 10 µVrms in the AP band from 300 Hz to 6 kHz, and 15.1 µVrms in the local field potential (LFP) band from 1 Hz to 300 Hz. To reach these noise levels the signals from the recording sites are routed out of the active array to dedicated low noise amplifiers in the periphery. Crosstalk between the related pixels is significantly reduced by individual actively shielded traces.

With vision impairment affecting millions of people world-wide, various strategies aiming at vision restoration are being undertaken. Thanks to decades of extensive research, electrical stimulation approaches to vision restoration began to undergo clinical trials. Quite recently, another technique employing optogenetic therapy emerged as a possible alternative. Both artificial vision restoration strategies reported poor spatial resolution so far. In this article, we compared the spatial resolution inferred ex vivo under ideal conditions using a computational model analysis of the retinal ganglion cell (RGC) spiking activity. The RGC spiking was stimulated in epiretinal configuration by either optogenetic or electrical means. RGCs activity was recorded from the ex vivo retina of transgenic late-stage photoreceptor-degenerated mice (rd10) using a high-density Complementary Metal Oxide Semiconductor (CMOS) based microelectrode array. The majority of retinal samples were stimulated by both, optogenetic and electrical stimuli using a spatial grating stimulus. A population-level analysis of the spiking activity of identified RGCs was performed and the spatial resolution achieved through electrical and optogenetic photo-stimulation was inferred using a support vector machine classifier. The best f1 score of the classifier for the electrical stimulation in epiretinal configuration was 86% for 32 micron wide gratings and increased to 100% for 128 microns. For optogenetically activated cells, we obtained high f1 scores of 82% for 10 microns grid width for a photo-stimulation frequency of 2.5 Hz and 73% for a photo-stimulation frequency of 10 Hz. A subsequent analysis, considering only the RGCs modulated in both electrical and optogenetic stimulation protocols revealed no significant difference in the prediction accuracy between the two stimulation modalities. The results presented here indicate that a high spatial resolution can be achieved for electrical or optogenetic artificial stimulation using the activated retinal ganglion cell output.

Recording neural signals from delicate autonomic nerves is a challenging task that requires the development of a low-invasive neural interface with highly selective, micrometer-sized electrodes. This paper reports on the development of a three-dimensional (3D) protruding thin-film microelectrode array (MEA), which is intended to be used for recording low-amplitude neural signals from pelvic nervous structures by penetrating the nerves transversely to reduce the distance to the axons. Cylindrical gold pillars (Ø 20 or 50 µm, ~60 µm height) were fabricated on a micromachined polyimide substrate in an electroplating process. Their sidewalls were insulated with parylene C, and their tips were optionally modified by wet etching and/or the application of a titanium nitride (TiN) coating. The microelectrodes modified by these combined techniques exhibited low impedances (~7 kΩ at 1 kHz for Ø 50 µm microelectrode with the exposed surface area of ~5000 µm²) and low intrinsic noise levels. Their functionalities were evaluated in an ex vivo pilot study with mouse retinae, in which spontaneous neuronal spikes were recorded with amplitudes of up to 66 µV. This novel process strategy for fabricating flexible, 3D neural interfaces with low-impedance microelectrodes has the potential to selectively record neural signals from not only delicate structures such as retinal cells but also autonomic nerves with improved signal quality to study neural circuits and develop stimulation strategies in bioelectronic medicine, e.g., for the control of vital digestive functions.

Retinal implants allow patients suffering from degenerative retinal diseases to regain visual percepts. Despite considerable effort in developing and improving retinal neuroprostheses in the last decades, the restored vision in patients does not achieve sufficient quality. The elicited percepts do not accurately match the stimulating pixels and therefore the formation of high acuity vision is hindered. One of the main obstacles in epiretinal implants is the concurrent activation of cells close to a stimulating electrode and cells that have their axons traversing the electrode. In this study, we use computational modeling to examine the effect of pulse duration on the selectivity of focal versus non-focal activation. Our results suggest that biphasic pulses in the range of 10-20 microseconds can prevent axonal activation while still reliably activating target neurons.

Stimulation of axons or its avoidance plays a central role for neuroprosthetics and neural-interfaces research. One peculiar example constitutes retinal implants. Retinal implants aim to artificially activate retinal ganglion cells (RGCs) via electrical stimulation. Such stimulation, however, often generates undesired stimulation of RGC axon bundles, which leads to distorted visual percepts. In order to establish stimulation strategies avoiding axonal stimulation it is necessary to image the evoked activity in single axons. In this work we electrically imaged axonal stimulation in ex vivo mouse retina using a high-density CMOS-based microelectrode array. We demonstrate signal propagation tracking via stimulus triggered average during high frequency (100 Hz) sinusoidal electrical stimulation.

Millions of people worldwide are diagnosed with retinal dystrophies such as retinitis pigmentosa and age-related macular degeneration. A retinal prosthesis using organic photovoltaic (OPV) semiconductors is a promising therapeutic device to restore vision to patients at the late onset of the disease. However, an appropriate cytotoxicity approach has to be employed on the OPV materials before using them as retinal implants. In this study, we followed ISO standards to assess the cytotoxicity of D18, Y6, PFN-Br and PDIN individually, and as mixtures of D18/Y6, D18/Y6/PFN-Br and D18/Y6/PDIN. These materials were proven for their high performance as organic solar cells. Human RPE cells were put in direct and indirect contact with these materials to analyze their cytotoxicity by the MTT assay, apoptosis by flow cytometry, and measurements of cell morphology and proliferation by immunofluorescence. We also assessed electrophysiological recordings on mouse retinal explants via microelectrode arrays (MEAs) coated with D18/Y6. In contrast to PFN-Br and PDIN, all in vitro experiments show no cytotoxicity of D18 and Y6 alone or as a D18/Y6 mixture. We conclude that D18/Y6 is safe to be subsequently investigated as a retinal prosthesis.

The most promising quantum algorithms require quantum processors that host millions of quantum bits when targeting practical applications1. A key challenge towards large-scale quantum computation is the interconnect complexity. In current solid-state qubit implementations, an important interconnect bottleneck appears between the quantum chip in a dilution refrigerator and the room-temperature electronics. Advanced lithography supports the fabrication of both control electronics and qubits in silicon using technology compatible with complementary metal oxide semiconductors (CMOS)2. When the electronics are designed to operate at cryogenic temperatures, they can ultimately be integrated with the qubits on the same die or package, overcoming the 'wiring bottleneck'3-6. Here we report a cryogenic CMOS control chip operating at 3 kelvin, which outputs tailored microwave bursts to drive silicon quantum bits cooled to 20 millikelvin. We first benchmark the control chip and find an electrical performance consistent with qubit operations of 99.99 per cent fidelity, assuming ideal qubits. Next, we use it to coherently control actual qubits encoded in the spin of single electrons confined in silicon quantum dots7-9 and find that the cryogenic control chip achieves the same fidelity as commercial instruments at room temperature. Furthermore, we demonstrate the capabilities of the control chip by programming a number of benchmarking protocols, as well as the Deutsch-Josza algorithm10, on a two-qubit quantum processor. These results open up the way towards a fully integrated, scalable silicon-based quantum computer.

Objective. Most neuroprosthetic implants employ pulsatile square-wave electrical stimuli, which are significantly different from physiological inter-neuronal communication. In case of retinal neuroprosthetics, which use a certain type of pulsatile stimuli, reliable object and contrast discrimination by implanted blind patients remained challenging. Here we investigated to what extent simple objects can be discriminated from the output of retinal ganglion cells (RGCs) upon sinusoidal stimulation. Approach. Spatially confined objects were formed by different combinations of 1024 stimulating microelectrodes. The RGC activity in the ex vivo retina of photoreceptor-degenerated mouse, of healthy mouse or of primate was recorded simultaneously using an interleaved recording microelectrode array implemented in a CMOS-based chip. Main results. We report that application of sinusoidal electrical stimuli (40 Hz) in epiretinal configuration instantaneously and reliably modulates the RGC activity in spatially confined areas at low stimulation threshold charge densities (40 nC mm−2). Classification of overlapping but spatially displaced objects (1° separation) was achieved by distinct spiking activity of selected RGCs. A classifier (regularized logistic regression) discriminated spatially displaced objects (size: 5.5° or 3.5°) with high accuracy (90% or 62%). Stimulation with low artificial contrast (10%) encoded by different stimulus amplitudes generated RGC activity, which was classified with an accuracy of 80% for large objects (5.5°). Significance. We conclude that time-continuous smooth-wave stimulation provides robust, localized neuronal activation in photoreceptor-degenerated retina, which may enable future artificial vision at high temporal, spatial and contrast resolution.

Solid-state qubits integrated on semiconductor substrates currently require at least one wire from every qubit to the control electronics, leading to a so-called wiring bottleneck for scaling. Demultiplexing via on-chip circuitry offers an effective strategy to overcome this bottleneck. In the case of gate-defined quantum dot arrays, specific static voltages need to be applied to many gates simultaneously to realize electron confinement. When a charge-locking structure is placed between the quantum device and the demultiplexer, the voltage can be maintained locally. In this study, we implement a switched-capacitor circuit for charge-locking and use it to float the plunger gate of a single quantum dot. Parallel plate capacitors, transistors and quantum dot devices are monolithically fabricated on a Si/SiGe-based substrate to avoid complex off-chip routing. We experimentally study the effects of the capacitor and transistor size on the voltage accuracy of the floating node. Furthermore, we demonstrate that the electrochemical potential of the quantum dot can follow a 100 Hz pulse signal while the dot is partially floating, which is essential for applying this strategy in qubit experiments.

Building a large-scale quantum computer requires the co-optimization of both the quantum bits (qubits) and their control electronics. By operating the CMOS control circuits at cryogenic temperatures (cryo-CMOS), and hence in close proximity to the cryogenic solid-state qubits, a compact quantum-computing system can be achieved, thus promising scalability to the large number of qubits required in a practical application. This work presents a cryo-CMOS microwave signal generator for frequency-multiplexed control of 4 × 32 qubits (32 qubits per RF output). A digitally intensive architecture offering full programmability of phase, amplitude, and frequency of the output microwave pulses and a wideband RF front end operating from 2 to 20 GHz allow targeting both spin qubits and transmons. The controller comprises a qubit-phase-tracking direct digital synthesis (DDS) back end for coherent qubit control and a single-sideband (SSB) RF front end optimized for minimum leakage between the qubit channels. Fabricated in Intel 22-nm FinFET technology, it achieves a 48-dB SNR and 45-dB spurious-free dynamic range (SFDR) in a 1-GHz data bandwidth when operating at 3 K, thus enabling high-fidelity qubit control. By exploiting the on-chip 4096-instruction memory, the capability to translate quantum algorithms to microwave signals has been demonstrated by coherently controlling a spin qubit at both 14 and 18 GHz.

Brain function relies on circuits of spiking neurons with synapses playing the key role of merging transmission with memory storage and processing. Electronics has made important advances to emulate neurons and synapses and brain-computer interfacing concepts that interlink brain and brain-inspired devices are beginning to materialise. We report on memristive links between brain and silicon spiking neurons that emulate transmission and plasticity properties of real synapses. A memristor paired with a metal-thin film titanium oxide microelectrode connects a silicon neuron to a neuron of the rat hippocampus. Memristive plasticity accounts for modulation of connection strength, while transmission is mediated by weighted stimuli through the thin film oxide leading to responses that resemble excitatory postsynaptic potentials. The reverse brain-to-silicon link is established through a microelectrode-memristor pair. On these bases, we demonstrate a three-neuron brain-silicon network where memristive synapses undergo long-term potentiation or depression driven by neuronal firing rates.

Human cerebrospinal fluid (hCSF) have proven advantageous over conventional medium when culturing both rodent and human brain tissue. Increased excitability and synchronicity, similar to the active state exclusively recorded in vivo , reported in rodent slice and cell-cultures with hCSF as recording medium, indicates properties of the hCSF not matched by the artificial cerebrospinal fluid (aCSF) commonly used for electrophysiological recording. To evaluate the possible importance of using hCSF as electrophysiological recording medium of human brain tissue, we compared the general excitability in ex vivo human brain tissue slice cultures during perfusion with hCSF and aCSF. For measuring the general activity from a majority of neurons within neocortical and hippocampal human ex vivo slices we used a microelectrode array (MEA) recording technique with 252 electrodes covering an area of 3.2 x 3.2 mm 2 and a second CMOS-based MEA with 4225 electrodes on a 2 x 2 mm 2 area for detailed mapping of action potential waveforms. We found that hCSF increase the number of active neurons and the firing rate of the neurons in the slices as well as increasing the numbers of bursts while leaving the duration of the bursts unchanged. Interestingly, not only an increase in the overall activity in the slices was observed, but a reconfiguration of the network functionality could be detected with specific activation and inactivation of subpopulations of neuronal ensembles. In conclusion, hCSF is an important component to consider for future human tissue studies, especially for experiments designed to mimic the in vivo situation.

Quantum computers (QC), comprising qubits and a classical controller, can provide exponential speed-up in solving certain problems. Among solid-state qubits, transmons and spin-qubits are the most promising, operating ≪ 1K. A qubit can be implemented in a physical system with two distinct energy levels representing the |0 ⟩ and |1 ⟩ states, e.g. the up and down spin states of an electron. The qubit states can be manipulated with microwave pulses, whose frequency f matches the energy level spacing E = hf (Fig. 19.1.1). For transmons, f ∼ 6GHz, for spin qubits f ∼ 20GHz, with the desire to lower it in the future. Qubit operations can be represented as rotations in the Bloch sphere.

Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.