Electrochemical and electrophysiological considerations for clinical high channel count neural interfaces.

Electrophysiological recording and stimulation are the gold standard for functional mapping during surgical and therapeutic interventions as well as capturing cellular activity in the intact human brain. A critical component probing human brain activity is the interface material at the electrode contact that electrochemically transduces brain signals to and from free charge carriers in the measurement system. Here, we summarize state-of-the-art electrode array systems in the context of translation for use in recording and stimulating human brain activity. We leverage parametric studies with multiple electrode materials to shed light on the varied levels of suitability to enable high signal-to-noise electrophysiological recordings as well as safe electrophysiological stimulation delivery. We discuss the effects of electrode scaling for recording and stimulation in pursuit of high spatial resolution, channel count electrode interfaces, delineating the electrode-tissue circuit components that dictate the electrode performance. Finally, we summarize recent efforts in the connectorization and packaging for high channel count electrode arrays and provide a brief account of efforts toward wireless neuronal monitoring systems.

A Comprehensive Large Signal, Small Signal, and Noise Model for IGZO Thin Film Transistor Circuits.

We report a new physics-based model for dual-gate amorphous-indium gallium zinc oxide (a-IGZO) thin film transistors (TFTs) which we developed and fine-tuned through experimental implementation and benchtop characterization. We fabricated and characterized a variety of test patterns, including a-IGZO TFTs with varying gate widths (100-1000 µm) and channel lengths (5-50 µm), transmission-line-measurement patterns and ground-signal-ground (GSG) radio frequency (RF) patterns. We modeled the contact resistance as a function of bias, channel area, and temperature, and captured all operating regimes, used physics-based modeling adjusted for empirical data to capture the TFT characteristics including ambipolar subthreshold currents, graded interbias-regime current changes, threshold and flat-band voltages, the interface trap density, the gate leakage currents, the noise, and the relevant small signal parameters. To design high-precision circuits for biosensing, we validated the dc, small signal, and noise characteristics of the model. We simulated and fabricated a two-stage common source amplifier circuit with a common drain output buffer and compared the measured and simulated gain and phase performance, finding an excellent fit over a frequency range spanning 10 kHz-10 MHz.

Ultra-Sharp Nanowire Arrays Natively Permeate, Record, and Stimulate Intracellular Activity in Neuronal and Cardiac Networks.

We report innovative scalable, vertical, ultra-sharp nanowire arrays that are individually addressable to enable long-term, native recordings of intracellular potentials. Stable amplitudes of intracellular potentials from 3D tissue-like networks of neurons and cardiomyocytes are obtained. Individual electrical addressability is necessary for high-fidelity intracellular electrophysiological recordings. This study paves the way toward predictive, high-throughput, and low-cost electrophysiological drug screening platforms.

A 0.00179 mm2/Ch Chopper-Stabilized TDMA Neural Recording System with Dynamic EOV Cancellation and Predictive Mixed-Signal Impedance Boosting.

This article presents a digitally-assisted multi-channel neural recording system. The system uses a 16-channel chopper-stabilized Time Division Multiple Access (TDMA) scheme to record multiplexed neural signals into a single shared analog front end (AFE). The choppers reduce the total integrated noise across the modulated spectrum by 2.4× and 4.3× in Local Field Potential (LFP) and Action Potential (AP) bands, respectively. In addition, a novel impedance booster based on Sign-Sign least mean squares (LMS) adaptive filter (AF) predicts the input signal and pre-charges the AC-coupling capacitors. The impedance booster module increases the AFE input impedance by a factor of 39× with a 7.1% increase in area. The proposed system obviates the need for on-chip digital demodulation, filtering, and remodulation normally required to extract Electrode Offset Voltages (EOV) from multiplexed neural signals, thereby achieving 3.6× and 2.8× savings in both area and power, respectively, in the EOV filter module. The Sign-Sign LMS AF is reused to determine the system loop gain, which relaxes the feedback DAC accuracy requirements and saves 10.1× in power compared to conventional oversampled DAC truncation-error ΔΣ-modulator. The proposed SoC is designed and fabricated in 65 nm CMOS, and each channel occupies 0.00179 mm2 of active area. Each channel consumes 5.11 µW of power while achieving 2.19 µVrms and 2.4 µVrms of input referred noise (IRN) over AP and LFP bands. The resulting AP band noise efficiency factor (NEF) is 1.8. The proposed system is verified with acute in-vivo recordings in a Sprague-Dawley rat using parylene C based thin-film platinum nanorod microelectrodes.

Flexible, scalable, high channel count stereo-electrode for recording in the human brain.

Over the past decade, stereotactically placed electrodes have become the gold standard for deep brain recording and stimulation for a wide variety of neurological and psychiatric diseases. Current electrodes, however, are limited in their spatial resolution and ability to record from small populations of neurons, let alone individual neurons. Here, we report on an innovative, customizable, monolithically integrated human-grade flexible depth electrode capable of recording from up to 128 channels and able to record at a depth of 10 cm in brain tissue. This thin, stylet-guided depth electrode is capable of recording local field potentials and single unit neuronal activity (action potentials), validated across species. This device represents an advance in manufacturing and design approaches which extends the capabilities of a mainstay technology in clinical neurology.

Conductive electrospun polymer improves stem cell-derived cardiomyocyte function and maturation.

Despite numerous efforts to generate mature human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), cells often remain immature, electrically isolated, and may not reflect adult biology. Conductive polymers are attractive candidates to facilitate electrical communication between hPSC-CMs, especially at sub-confluent cell densities or diseased cells lacking cell-cell junctions. Here we electrospun conductive polymers to create a conductive fiber mesh and assess if electrical signal propagation is improved in hPSC-CMs seeded on the mesh network. Matrix characterization indicated fiber structure remained stable over weeks in buffer, scaffold stiffness remained near in vivo cardiac stiffness, and electrical conductivity scaled with conductive polymer concentration. Cells remained adherent and viable on the scaffolds for at least 5 days. Transcriptomic profiling of hPSC-CMs cultured on conductive substrates for 3 days showed upregulation of cardiac and muscle-related genes versus non-conductive fibers. Structural proteins were more organized and calcium handling was improved on conductive substrates, even at sub-confluent cell densities; prolonged culture on conductive scaffolds improved membrane depolarization compared to non-conductive substrates. Taken together, these data suggest that blended, conductive scaffolds are stable, supportive of electrical coupling in hPSC-CMs, and promote maturation, which may improve our ability to model cardiac diseases and develop targeted therapies.

A universal model of electrochemical safety limits in vivo for electrophysiological stimulation.

Electrophysiological stimulation has been widely adopted for clinical diagnostic and therapeutic treatments for modulation of neuronal activity. Safety is a primary concern in an interventional design leveraging the effects of electrical charge injection into tissue in the proximity of target neurons. While modalities of tissue damage during stimulation have been extensively investigated for specific electrode geometries and stimulation paradigms, a comprehensive model that can predict the electrochemical safety limits in vivo doesn't yet exist. Here we develop a model that accounts for the electrode geometry, inter-electrode separation, material, and stimulation paradigm in predicting safe current injection limits. We performed a parametric investigation of the stimulation limits in both benchtop and in vivo setups for flexible microelectrode arrays with low impedance, high geometric surface area platinum nanorods and PEDOT:PSS, and higher impedance, planar platinum contacts. We benchmark our findings against standard clinical electrocorticography and depth electrodes. Using four, three and two contact electrochemical impedance measurements and comprehensive circuit models derived from these measurements, we developed a more accurate, clinically relevant and predictive model for the electrochemical interface potential. For each electrode configuration, we experimentally determined the geometric correction factors that dictate geometry-enforced current spreading effects. We also determined the electrolysis window from cyclic-voltammetry measurements which allowed us to calculate stimulation current safety limits from voltage transient measurements. From parametric benchtop electrochemical measurements and analyses for different electrode types, we created a predictive equation for the cathodal excitation measured at the electrode interface as a function of the electrode dimensions, geometric factor, material and stimulation paradigm. We validated the accuracy of our equation in vivo and compared the experimentally determined safety limits to clinically used stimulation protocols. Our new model overcomes the design limitations of Shannon's equation and applies to macro- and micro-electrodes at different density or separation of contacts, captures the breakdown of charge-density based approaches at long stimulation pulse widths, and invokes appropriate power exponents to current, pulse width, and material/electrode-dependent impedance.

Electrochemical safety limits for clinical stimulation investigated using depth and strip electrodes in the pig brain.

Objective. Diagnostic and therapeutic electrical stimulation are increasingly utilized with the rise of neuromodulation devices. However, systematic investigations that depict the practical clinical stimulation paradigms (bipolar, two-electrode configuration) to determine the safety limits are currently lacking. Further, safe charge densities that were classically determined from conical sharp electrodes are generalized for cylindrical (depth) and flat (surface grid) electrodes completely ignoring geometric factors that govern current spreading and trajectories in tissue.Approach. This work reports the first investigations comparing stimulation limits for clinically used electrodes in two mediums: in benchtop experiments in saline andin vivoin a single acute experiment in the pig brain. We experimentally determine the geometric factors, the water electrolysis windows, and the current safety limits from voltage transients, for the sEEG, depth and surface strip electrodes in both mediums. Using four-electrode and three-electrode configuration measurements and comprehensive circuit models that accurately depict our measurements, we delineate the various elements of the stimulation medium, including the tissue-electrode interface impedance spectra, the medium impedance and the bias-dependent change in the interface impedance as a function of stimulation parameters.Main results. The results of our systematics studies suggest that safe currents in clinical bipolar stimulation determinedin vivocan be as much as 24 times smaller than those determined from benchtop experiments (for depth electrodes at a 1 ms pulse duration). Our detailed circuit modeling attributes this drastic difference in safe limits to the greatly dissimilar electrode/tissue and electrode/saline impedances.Significance. We established the electrochemical safety limits for commonly used clinical electrodesin vivoand revealed by detailied electrochemical modeling how they differ from benchtop evaluation. We argue that electrochemical limits and currents are unique for each electrode, should be measuredin vivoaccording to the protocols established in this work, and should be accounted for while setting the stimulation parameters for clinical applications including for chronic applications.

Considerations and recent advances in nanoscale interfaces with neuronal and cardiac networks.

Nanoscale interfaces with biological tissue, principally made with nanowires (NWs), are envisioned as minimally destructive to the tissue and as scalable tools to directly transduce the electrochemical activity of a neuron at its finest resolution. This review lays the foundations for understanding the material and device considerations required to interrogate neuronal activity at the nanoscale. We first discuss the electrochemical nanoelectrode-neuron interfaces and then present new results concerning the electrochemical impedance and charge injection capacities of millimeter, micrometer, and nanometer scale wires with Pt, PEDOT:PSS, Si, Ti, ITO, IrO x , Ag, and AgCl materials. Using established circuit models for NW-neuron interfaces, we discuss the impact of having multiple NWs interfacing with a single neuron on the amplitude and temporal characteristics of the recorded potentials. We review state of the art advances in nanoelectrode-neuron interfaces, the standard control experiments to investigate their electrophysiological behavior, and present recent high fidelity recordings of intracellular potentials obtained with ultrasharp NWs developed in our laboratory that naturally permeate neuronal cell bodies. Recordings from arrays and individually addressable electrically shorted NWs are presented, and the long-term stability of intracellular recording is discussed and put in the context of established techniques. Finally, a perspective on future research directions and applications is presented.