Flexible, high-resolution cortical arrays with large coverage capture microscale high-frequency oscillations in patients with epilepsy.

OBJECTIVE: Effective surgical treatment of drug-resistant epilepsy depends on accurate localization of the epileptogenic zone (EZ). High-frequency oscillations (HFOs) are potential biomarkers of the EZ. Previous research has shown that HFOs often occur within submillimeter areas of brain tissue and that the coarse spatial sampling of clinical intracranial electrode arrays may limit the accurate capture of HFO activity. In this study, we sought to characterize microscale HFO activity captured on thin, flexible microelectrocorticographic (µECoG) arrays, which provide high spatial resolution over large cortical surface areas. METHODS: We used novel liquid crystal polymer thin-film µECoG arrays (.76-1.72-mm intercontact spacing) to capture HFOs in eight intraoperative recordings from seven patients with epilepsy. We identified ripple (80-250 Hz) and fast ripple (250-600 Hz) HFOs using a common energy thresholding detection algorithm along with two stages of artifact rejection. We visualized microscale subregions of HFO activity using spatial maps of HFO rate, signal-to-noise ratio, and mean peak frequency. We quantified the spatial extent of HFO events by measuring covariance between detected HFOs and surrounding activity. We also compared HFO detection rates on microcontacts to simulated macrocontacts by spatially averaging data. RESULTS: We found visually delineable subregions of elevated HFO activity within each µECoG recording. Forty-seven percent of HFOs occurred on single 200-µm-diameter recording contacts, with minimal high-frequency activity on surrounding contacts. Other HFO events occurred across multiple contacts simultaneously, with covarying activity most often limited to a .95-mm radius. Through spatial averaging, we estimated that macrocontacts with 2-3-mm diameter would only capture 44% of the HFOs detected in our µECoG recordings. SIGNIFICANCE: These results demonstrate that thin-film microcontact surface arrays with both highresolution and large coverage accurately capture microscale HFO activity and may improve the utility of HFOs to localize the EZ for treatment of drug-resistant epilepsy.

Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex.

Bioresorbable silicon electronics technology offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort associated with surgical extraction. Applications include postoperative monitoring and transient physiologic recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopaedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, which record in vivo electrophysiological signals from the cortical surface and the subgaleal space. The devices detect normal physiologic and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to standard clinical systems and reduced tissue reactivity relative to conventional clinical electrocorticography (ECoG) electrodes. This technology offers general applicability in neural interfaces, with additional potential utility in treatment of disorders where transient monitoring and modulation of physiologic function, implant integrity and tissue recovery or regeneration are required.

High-density cortical µECoG arrays concurrently track spreading depolarizations and long-term evolution of stroke in awake rats.

Spreading depolarizations (SDs) are widely recognized as a major contributor to the progression of tissue damage from ischemic stroke even if blood flow can be restored. They are characterized by negative intracortical waveforms of up to -20 mV, propagation velocities of 3 - 6 mm/min, and massive disturbance of membrane ion homeostasis. High-density, micro-electrocorticographic (µECoG) epidural electrodes and custom, DC-coupled, multiplexed amplifiers, were used to continuously characterize and monitor SD and µECoG cortical signal evolution in awake, moving rats over days. This highly innovative approach can define these events over a large brain surface area (~ 3.4 × 3.4 mm), extending across the boundaries of the stroke, and offers sufficient electrode density (60 contacts total per array for a density of 5.7 electrodes / mm2) to measure and determine the origin of SDs in relation to the infarct boundaries. In addition, spontaneous ECoG activity can simultaneously be detected to further define cortical infarct regions. This technology allows us to understand dynamic stroke evolution and provides immediate cortical functional activity over days. Further translational development of this approach may facilitate improved treatment options for acute stroke patients.

A Soft, High-Density Neuroelectronic Array.

Techniques to study brain activities have evolved dramatically, yet tremendous challenges remain in acquiring high-throughput electrophysiological recordings minimally invasively. Here, we develop an integrated neuroelectronic array that is filamentary, high-density and flexible. Specifically, with a design of single-transistor multiplexing and current sensing, the total 256 neuroelectrodes achieve only a 2.3 × 0.3 mm2 area, unprecedentedly on a flexible substrate. A novel single-transistor multiplexing acquisition circuit further reduces noise from the electrodes, decreased the footprint of each pixel, and potentially increased the device lifetime. The filamentary neuroelectronic array also integrates with a rollable contact pad design, allowing the device to be injected through a syringe, enabling potential minimally invasive array delivery. Successful acute auditory experiments in rats validate the ability of the array to record neural signals with high tone decoding accuracy. Together, these results establish soft, high-density neuroelectronic arrays as promising devices for neuroscience research and clinical applications.

High-resolution neural recordings improve the accuracy of speech decoding.

Patients suffering from debilitating neurodegenerative diseases often lose the ability to communicate, detrimentally affecting their quality of life. One solution to restore communication is to decode signals directly from the brain to enable neural speech prostheses. However, decoding has been limited by coarse neural recordings which inadequately capture the rich spatio-temporal structure of human brain signals. To resolve this limitation, we performed high-resolution, micro-electrocorticographic (µECoG) neural recordings during intra-operative speech production. We obtained neural signals with 57× higher spatial resolution and 48% higher signal-to-noise ratio compared to macro-ECoG and SEEG. This increased signal quality improved decoding by 35% compared to standard intracranial signals. Accurate decoding was dependent on the high-spatial resolution of the neural interface. Non-linear decoding models designed to utilize enhanced spatio-temporal neural information produced better results than linear techniques. We show that high-density µECoG can enable high-quality speech decoding for future neural speech prostheses.

High-Density, Actively Multiplexed µECoG Array on Reinforced Silicone Substrate.

Simultaneous interrogation of electrical signals from wide areas of the brain is vital for neuroscience research and can aid in understanding the mechanisms of brain function and treatments for neurological disorders. There emerges a demand for development of devices with highly conformal interfaces that can span large cortical regions, have sufficient spatial resolution, and chronic recording capability while keeping a small implantation footprint. In this work, we have designed 61 channel and 48 channel high-density, cortical, micro-electrocorticographic electrode arrays with 400 µm pitch on an ultra-soft but durable substrate. We have also developed a custom multiplexing integrated circuit (IC), methods for packaging the IC in a water-tight liquid crystal polymer casing, and a micro-bonding method for attaching the electronics package to the electrode array. With the integrated multiplexer, the number of external wire connections can be reduced to 16 wires, thereby diminishing the invasive footprint of the device. Both the electrode array and IC were tested in vivo in a rat model to demonstrate the ability to sense finely-localized electrophysiological signals.

Intraoperative microseizure detection using a high-density micro-electrocorticography electrode array.

One-third of epilepsy patients suffer from medication-resistant seizures. While surgery to remove epileptogenic tissue helps some patients, 30-70% of patients continue to experience seizures following resection. Surgical outcomes may be improved with more accurate localization of epileptogenic tissue. We have previously developed novel thin-film, subdural electrode arrays with hundreds of microelectrodes over a 100-1000 mm2 area to enable high-resolution mapping of neural activity. Here, we used these high-density arrays to study microscale properties of human epileptiform activity. We performed intraoperative micro-electrocorticographic recordings in nine patients with epilepsy. In addition, we recorded from four patients with movement disorders undergoing deep brain stimulator implantation as non-epileptic controls. A board-certified epileptologist identified microseizures, which resembled electrographic seizures normally observed with clinical macroelectrodes. Recordings in epileptic patients had a significantly higher microseizure rate (2.01 events/min) than recordings in non-epileptic subjects (0.01 events/min; permutation test, P = 0.0068). Using spatial averaging to simulate recordings from larger electrode contacts, we found that the number of detected microseizures decreased rapidly with increasing contact diameter and decreasing contact density. In cases in which microseizures were spatially distributed across multiple channels, the approximate onset region was identified. Our results suggest that micro-electrocorticographic electrode arrays with a high density of contacts and large coverage are essential for capturing microseizures in epilepsy patients and may be beneficial for localizing epileptogenic tissue to plan surgery or target brain stimulation.

Sufficient sampling for kriging prediction of cortical potential in rat, monkey, and human µECoG.

Objective. Large channel count surface-based electrophysiology arrays (e.g. µECoG) are high-throughput neural interfaces with good chronic stability. Electrode spacing remains ad hoc due to redundancy and nonstationarity of field dynamics. Here, we establish a criterion for electrode spacing based on the expected accuracy of predicting unsampled field potential from sampled sites.Approach. We applied spatial covariance modeling and field prediction techniques based on geospatial kriging to quantify sufficient sampling for thousands of 500 ms µECoG snapshots in human, monkey, and rat. We calculated a probably approximately correct (PAC) spacing based on kriging that would be required to predict µECoG fields at≤10% error for most cases (95% of observations).Main results. Kriging theory accurately explained the competing effects of electrode density and noise on predicting field potential. Across five frequency bands from 4-7 to 75-300 Hz, PAC spacing was sub-millimeter for auditory cortex in anesthetized and awake rats, and posterior superior temporal gyrus in anesthetized human. At 75-300 Hz, sub-millimeter PAC spacing was required in all species and cortical areas.Significance. PAC spacing accounted for the effect of signal-to-noise on prediction quality and was sensitive to the full distribution of non-stationary covariance states. Our results show that µECoG arrays should sample at sub-millimeter resolution for applications in diverse cortical areas and for noise resilience.

Flexible, high-resolution thin-film electrodes for human and animal neural research.

Objective.Brain functions such as perception, motor control, learning, and memory arise from the coordinated activity of neuronal assemblies distributed across multiple brain regions. While major progress has been made in understanding the function of individual neurons, circuit interactions remain poorly understood. A fundamental obstacle to deciphering circuit interactions is the limited availability of research tools to observe and manipulate the activity of large, distributed neuronal populations in humans. Here we describe the development, validation, and dissemination of flexible, high-resolution, thin-film (TF) electrodes for recording neural activity in animals and humans.Approach.We leveraged standard flexible printed-circuit manufacturing processes to build high-resolution TF electrode arrays. We used biocompatible materials to form the substrate (liquid crystal polymer; LCP), metals (Au, PtIr, and Pd), molding (medical-grade silicone), and 3D-printed housing (nylon). We designed a custom, miniaturized, digitizing headstage to reduce the number of cables required to connect to the acquisition system and reduce the distance between the electrodes and the amplifiers. A custom mechanical system enabled the electrodes and headstages to be pre-assembled prior to sterilization, minimizing the setup time required in the operating room. PtIr electrode coatings lowered impedance and enabled stimulation. High-volume, commercial manufacturing enables cost-effective production of LCP-TF electrodes in large quantities.Main Results. Our LCP-TF arrays achieve 25× higher electrode density, 20× higher channel count, and 11× reduced stiffness than conventional clinical electrodes. We validated our LCP-TF electrodes in multiple human intraoperative recording sessions and have disseminated this technology to >10 research groups. Using these arrays, we have observed high-frequency neural activity with sub-millimeter resolution.Significance.Our LCP-TF electrodes will advance human neuroscience research and improve clinical care by enabling broad access to transformative, high-resolution electrode arrays.

Development of a neural interface for high-definition, long-term recording in rodents and nonhuman primates.

Long-lasting, high-resolution neural interfaces that are ultrathin and flexible are essential for precise brain mapping and high-performance neuroprosthetic systems. Scaling to sample thousands of sites across large brain regions requires integrating powered electronics to multiplex many electrodes to a few external wires. However, existing multiplexed electrode arrays rely on encapsulation strategies that have limited implant lifetimes. Here, we developed a flexible, multiplexed electrode array, called "Neural Matrix," that provides stable in vivo neural recordings in rodents and nonhuman primates. Neural Matrix lasts over a year and samples a centimeter-scale brain region using over a thousand channels. The long-lasting encapsulation (projected to last at least 6 years), scalable device design, and iterative in vivo optimization described here are essential components to overcoming current hurdles facing next-generation neural technologies.

A Novel µECoG Electrode Interface for Comparison of Local and Common Averaged Referenced Signals.

Micro-electrocorticography (µECoG) is a minimally invasive neural interface that allows for recording from the surface of the brain with high spatial and temporal resolution [1], [2]. However, discerning multi-unit and local field potential (LFP) activity with potentially highly-correlated signals across a dense µECoG array can be challenging. Here we describe a novel µECoG design to compare the effect of referencing recordings to a local reference electrode and common average referencing (CAR). The filtering effect and the significant increase in signal to noise ratio of the evoked response (ESNR) can be seen after re-referencing for both types of referencing. In a preliminary analysis, re-referencing the µECoG signals can increase recording performance at high contact densities in the auditory cortex. This also provides promising evidence for a versatile in-house fabricated µECoG electrode.

3D Printed Cranial Window System for Chronic µECoG Recording.

Chronic studies of flexible µECoG electrodes and the electrode-brain interface have been limited by the inability to assess tissue response over time. The electrophysiological system presented here combines epidural microelectrocorticographic (µECoG) recording capabilities with the ability to visualize tissue response over time through light microscopy and optical coherence tomography (OCT). With the ability to interchange both the electrode and the electronics, and a flushing port for injection of flushing saline and/or drugs, this 3D printed system has future applications in chronic electrophysiology, optogenetics, and advanced imaging methods.

Long-term recording reliability of liquid crystal polymer µECoG arrays.

OBJECTIVE: The clinical use of microsignals recorded over broad cortical regions is largely limited by the chronic reliability of the implanted interfaces. APPROACH: We evaluated the chronic reliability of novel 61-channel micro-electrocorticographic (µECoG) arrays in rats chronically implanted for over one year and using accelerated aging. Devices were encapsulated with polyimide (PI) or liquid crystal polymer (LCP), and fabricated using commercial manufacturing processes. In vitro failure modes and predicted lifetimes were determined from accelerated soak testing. Successful designs were implanted epidurally over the rodent auditory cortex. Trends in baseline signal level, evoked responses and decoding performance were reported for over one year of implantation. MAIN RESULTS: Devices fabricated with LCP consistently had longer in vitro lifetimes than PI encapsulation. Our accelerated aging results predicted device integrity beyond 3.4 years. Five implanted arrays showed stable performance over the entire implantation period (247-435 d). Our regression analysis showed that impedance predicted signal quality and information content only in the first 31 d of recordings and had little predictive value in the chronic phase (>31 d). In the chronic phase, site impedances slightly decreased yet decoding performance became statistically uncorrelated with impedance. We also employed an improved statistical model of spatial variation to measure sensitivity to locally varying fields, which is typically concealed in standard signal power calculations. SIGNIFICANCE: These findings show that µECoG arrays can reliably perform in chronic applications in vivo for over one year, which facilitates the development of a high-density, clinically viable interface.

A low-cost, scalable, current-sensing digital headstage for high channel count µECoG.

OBJECTIVE: High channel count electrode arrays allow for the monitoring of large-scale neural activity at high spatial resolution. Implantable arrays featuring many recording sites require compact, high bandwidth front-end electronics. In the present study, we investigated the use of a small, light weight, and low cost digital current-sensing integrated circuit for acquiring cortical surface signals from a 61-channel micro-electrocorticographic (µECoG) array. APPROACH: We recorded both acute and chronic µECoG signal from rat auditory cortex using our novel digital current-sensing headstage. For direct comparison, separate recordings were made in the same anesthetized preparations using an analog voltage headstage. A model of electrode impedance explained the transformation between current- and voltage-sensed signals, and was used to reconstruct cortical potential. We evaluated the digital headstage using several metrics of the baseline and response signals. MAIN RESULTS: The digital current headstage recorded neural signal with similar spatiotemporal statistics and auditory frequency tuning compared to the voltage signal. The signal-to-noise ratio of auditory evoked responses (AERs) was significantly stronger in the current signal. Stimulus decoding based on true and reconstructed voltage signals were not significantly different. Recordings from an implanted system showed AERs that were detectable and decodable for 52 d. The reconstruction filter mitigated the thermal current noise of the electrode impedance and enhanced overall SNR. SIGNIFICANCE: We developed and validated a novel approach to headstage acquisition that used current-input circuits to independently digitize 61 channels of µECoG measurements of the cortical field. These low-cost circuits, intended to measure photo-currents in digital imaging, not only provided a signal representing the local cortical field with virtually the same sensitivity and specificity as a traditional voltage headstage but also resulted in a small, light headstage that can easily be scaled to record from hundreds of channels.

Capacitively Coupled Arrays of Multiplexed Flexible Silicon Transistors for Long-Term Cardiac Electrophysiology.

Advanced capabilities in electrical recording are essential for the treatment of heart-rhythm diseases. The most advanced technologies use flexible integrated electronics; however, the penetration of biological fluids into the underlying electronics and any ensuing electrochemical reactions pose significant safety risks. Here, we show that an ultrathin, leakage-free, biocompatible dielectric layer can completely seal an underlying layer of flexible electronics while allowing for electrophysiological measurements through capacitive coupling between tissue and the electronics, and thus without the need for direct metal contact. The resulting current-leakage levels and operational lifetimes are, respectively, four orders of magnitude smaller and between two and three orders of magnitude longer than those of any other flexible-electronics technology. Systematic electrophysiological studies with normal, paced and arrhythmic conditions in Langendorff hearts highlight the capabilities of the capacitive-coupling approach. Our technology provides a realistic pathway towards the broad applicability of biocompatible, flexible electronic implants.

Human sensory-evoked responses differ coincident with either "fusion-memory" or "flash-memory", as shown by stimulus repetition-rate effects.

BACKGROUND: A new method has been used to obtain human sensory evoked-responses whose time-domain waveforms have been undetectable by previous methods. These newly discovered evoked-responses have durations that exceed the time between the stimuli in a continuous stream, thus causing an overlap which, up to now, has prevented their detection. We have named them "A-waves", and added a prefix to show the sensory system from which the responses were obtained (visA-waves, audA-waves, somA-waves). RESULTS: When A-waves were studied as a function of stimulus repetition-rate, it was found that there were systematic differences in waveshape at repetition-rates above and below the psychophysical region in which the sensation of individual stimuli fuse into a continuity. The fusion phenomena is sometimes measured by a "Critical Fusion Frequency", but for this research we can only identify a frequency-region [which we call the STZ (Sensation-Transition Zone)]. Thus, the A-waves above the STZ differed from those below the STZ, as did the sensations. Study of the psychophysical differences in auditory and visual stimuli, as shown in this paper, suggest that different stimulus features are detected, and remembered, at stimulation rates above and below STZ. CONCLUSION: The results motivate us to speculate that: 1) Stimulus repetition-rates above the STZ generate waveforms which underlie "fusion-memory" whereas rates below the STZ show neuronal processing in which "flash-memory" occurs. 2) These two memories differ in both duration and mechanism, though they may occur in the same cell groups. 3) The differences in neuronal processing may be related to "figure" and "ground" differentiation. We conclude that A-waves provide a novel measure of neural processes that can be detected on the human scalp, and speculate that they may extend clinical applications of evoked response recordings. If A-waves also occur in animals, it is likely that A-waves will provide new methods for comparison of activity of neuronal populations and single cells.

In vitro assessment of long-term reliability of low-cost µECoG arrays.

Micro-electrocorticographic (µECοG) electrode arrays provide a minimally invasive, high-resolution neural interface with broad cortical coverage. Previously, we fabricated µECoG arrays at a lower cost than commercially available devices using low-cost industrial processes [1], [2]. Here, we report the in vitro electrical performance of five µECoG designs undergoing an accelerated aging protocol. The impedance and yield of the µECoG arrays were tracked over time. The equivalent lifetime at 37°C depended on the manufacturer and material stack-up, and ranged between 30 and greater than 760 days (ongoing). The main failure modes of these devices were delamination at the site of the electrode contact and broken traces due to metal dissolution. Based on these in vitro results, we offer several recommendations for µECoG designs suitable for chronic implantation.

A low-cost, multiplexed µECoG system for high-density recordings in freely moving rodents.

OBJECTIVE: Micro-electrocorticography (µECoG) offers a minimally invasive neural interface with high spatial resolution over large areas of cortex. However, electrode arrays with many contacts that are individually wired to external recording systems are cumbersome and make recordings in freely behaving rodents challenging. We report a novel high-density 60-electrode system for µECoG recording in freely moving rats. APPROACH: Multiplexed headstages overcome the problem of wiring complexity by combining signals from many electrodes to a smaller number of connections. We have developed a low-cost, multiplexed recording system with 60 contacts at 406 µm spacing. We characterized the quality of the electrode signals using multiple metrics that tracked spatial variation, evoked-response detectability, and decoding value. Performance of the system was validated both in anesthetized animals and freely moving awake animals. MAIN RESULTS: We recorded µECoG signals over the primary auditory cortex, measuring responses to acoustic stimuli across all channels. Single-trial responses had high signal-to-noise ratios (SNR) (up to 25 dB under anesthesia), and were used to rapidly measure network topography within ∼10 s by constructing all single-channel receptive fields in parallel. We characterized evoked potential amplitudes and spatial correlations across the array in the anesthetized and awake animals. Recording quality in awake animals was stable for at least 30 days. Finally, we used these responses to accurately decode auditory stimuli on single trials. SIGNIFICANCE: This study introduces (1) a µECoG recording system based on practical hardware design and (2) a rigorous analytical method for characterizing the signal characteristics of µECoG electrode arrays. This methodology can be applied to evaluate the fidelity and lifetime of any µECoG electrode array. Our µECoG-based recording system is accessible and will be useful for studies of perception and decision-making in rodents, particularly over the entire time course of behavioral training and learning.

The use of QSD (q-sequence deconvolution) to recover superposed, transient evoked-responses.

OBJECTIVE: We describe q-sequence deconvolution (QSD), a new data acquisition/analysis method for evoked-responses that solves the problem of waveform distortion at high stimulus repetition-rates, due to response overlap. QSD can increase the sensitivity of clinically useful evoked-responses because it is well known that high stimulus repetition-rates are better for detecting pathophysiology. METHODS: QSD is applicable to a variety of experimental conditions. Because some QSD-parameters must be chosen by the experimenter, the underlying principles and assumptions of the method are described in detail. The theoretical and mathematical bases of the QSD method are also described, including some equivalent computational formulations. RESULTS: QSD was applied to recordings of the human auditory brainstem response (ABR) at stimulus repetition-rates that overlapped the responses. The transient ABR was recovered at all rates tested (highest 160/s), and showed systematic changes with stimulus repetition-rate within a single subject. CONCLUSIONS: QSD offers a new method of recovering brain evoked-response activity having a duration longer than the time between stimuli. SIGNIFICANCE: The use of this new technique for analysis of evoked responses will permit examination of brain activation patterns across a broad range of stimulus repetition-rates, some never before studied. Such studies will improve the sensitivity of evoked-responses for the detection of brain pathophysiology. New measures of brain activity may be discovered using QSD. The method also permits the recovery of the transient brain waveforms that overlap to form 'steady-state' waveforms. An additional benefit of the QSD method is that repetition-rate can be isolated as a variable, independent of other stimulus characteristics, even if the response is a nonlinear function of rate.

Cross-correlation based µECoG waveform tracking.

Clinical electrodes for epileptic seizure monitoring traditionally require a tradeoff between coverage area and spatial resolution. However, with multiplexed, flexible array devices, high spatial resolution is possible over large surface areas. This high resolution data, recorded from 360 electrodes or more, is difficult to review manually for subtle patterns. Here we develop innovative methods for visualizing micro-electrocorticography (µECoG) datasets. The data contains seizure and non-seizure dynamics that can be used to better understand how seizures begin, progress, and end. Novel visualization techniques allow the researcher to better understand the data by arranging it in accessible ways. This paper presents tools to visualize a seizure waveform's velocity and location over a given window of time.