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.

Flexible electronic/optoelectronic microsystems with scalable designs for chronic biointegration.

Flexible biocompatible electronic systems that leverage key materials and manufacturing techniques associated with the consumer electronics industry have potential for broad applications in biomedicine and biological research. This study reports scalable approaches to technologies of this type, where thin microscale device components integrate onto flexible polymer substrates in interconnected arrays to provide multimodal, high performance operational capabilities as intimately coupled biointerfaces. Specificially, the material options and engineering schemes summarized here serve as foundations for diverse, heterogeneously integrated systems. Scaled examples incorporate >32,000 silicon microdie and inorganic microscale light-emitting diodes derived from wafer sources distributed at variable pitch spacings and fill factors across large areas on polymer films, at full organ-scale dimensions such as human brain, over ∼150 cm2 In vitro studies and accelerated testing in simulated biofluids, together with theoretical simulations of underlying processes, yield quantitative insights into the key materials aspects. The results suggest an ability of these systems to operate in a biologically safe, stable fashion with projected lifetimes of several decades without leakage currents or reductions in performance. The versatility of these combined concepts suggests applicability to many classes of biointegrated semiconductor devices.

Conductively coupled flexible silicon electronic systems for chronic neural electrophysiology.

Materials and structures that enable long-term, intimate coupling of flexible electronic devices to biological systems are critically important to the development of advanced biomedical implants for biological research and for clinical medicine. By comparison with simple interfaces based on arrays of passive electrodes, the active electronics in such systems provide powerful and sometimes essential levels of functionality; they also demand long-lived, perfect biofluid barriers to prevent corrosive degradation of the active materials and electrical damage to the adjacent tissues. Recent reports describe strategies that enable relevant capabilities in flexible electronic systems, but only for capacitively coupled interfaces. Here, we introduce schemes that exploit patterns of highly doped silicon nanomembranes chemically bonded to thin, thermally grown layers of SiO2 as leakage-free, chronically stable, conductively coupled interfaces. The results can naturally support high-performance, flexible silicon electronic systems capable of amplified sensing and active matrix multiplexing in biopotential recording and in stimulation via Faradaic charge injection. Systematic in vitro studies highlight key considerations in the materials science and the electrical designs for high-fidelity, chronic operation. The results provide a versatile route to biointegrated forms of flexible electronics that can incorporate the most advanced silicon device technologies with broad applications in electrical interfaces to the brain and to other organ systems.

Ultrathin, transferred layers of thermally grown silicon dioxide as biofluid barriers for biointegrated flexible electronic systems.

Materials that can serve as long-lived barriers to biofluids are essential to the development of any type of chronic electronic implant. Devices such as cardiac pacemakers and cochlear implants use bulk metal or ceramic packages as hermetic enclosures for the electronics. Emerging classes of flexible, biointegrated electronic systems demand similar levels of isolation from biofluids but with thin, compliant films that can simultaneously serve as biointerfaces for sensing and/or actuation while in contact with the soft, curved, and moving surfaces of target organs. This paper introduces a solution to this materials challenge that combines (i) ultrathin, pristine layers of silicon dioxide (SiO2) thermally grown on device-grade silicon wafers, and (ii) processing schemes that allow integration of these materials onto flexible electronic platforms. Accelerated lifetime tests suggest robust barrier characteristics on timescales that approach 70 y, in layers that are sufficiently thin (less than 1 µm) to avoid significant compromises in mechanical flexibility or in electrical interface fidelity. Detailed studies of temperature- and thickness-dependent electrical and physical properties reveal the key characteristics. Molecular simulations highlight essential aspects of the chemistry that governs interactions between the SiO2 and surrounding water. Examples of use with passive and active components in high-performance flexible electronic devices suggest broad utility in advanced chronic implants.

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.

A high-density, high-channel count, multiplexed µECoG array for auditory-cortex recordings.

Our understanding of the large-scale population dynamics of neural activity is limited, in part, by our inability to record simultaneously from large regions of the cortex. Here, we validated the use of a large-scale active microelectrode array that simultaneously records 196 multiplexed micro-electrocortigraphical (µECoG) signals from the cortical surface at a very high density (1,600 electrodes/cm(2)). We compared µECoG measurements in auditory cortex using a custom "active" electrode array to those recorded using a conventional "passive" µECoG array. Both of these array responses were also compared with data recorded via intrinsic optical imaging, which is a standard methodology for recording sound-evoked cortical activity. Custom active µECoG arrays generated more veridical representations of the tonotopic organization of the auditory cortex than current commercially available passive µECoG arrays. Furthermore, the cortical representation could be measured efficiently with the active arrays, requiring as little as 13.5 s of neural data acquisition. Next, we generated spectrotemporal receptive fields from the recorded neural activity on the active µECoG array and identified functional organizational principles comparable to those observed using intrinsic metabolic imaging and single-neuron recordings. This new electrode array technology has the potential for large-scale, temporally precise monitoring and mapping of the cortex, without the use of invasive penetrating electrodes.

Intan Technologies integrated circuits can produce analog-to-digital conversion artifacts that affect neural signal acquisition.

OBJECTIVE: Intan Technologies' integrated circuits (ICs) are valuable tools for neurophysiological data acquisition, providing signal amplification, filtering, and digitization from many channels (up to 64 channels / chip) at high sampling rates (up to 30 kSPS) within a compact package (≤ 9x7 mm). However, we found that the analog-to-digital converters (ADCs) in the Intan RHD2000 series ICs can produce artifacts in recorded signals. Here, we examine the effects of these ADC artifacts on neural signal quality and describe a method to detect them in recorded data. Approach: We identified two types of ADC artifacts produced by Intan ICs: 1) jumps, resulting from missing output codes, and 2) flatlines, resulting from overrepresented output codes. We identified ADC artifacts in neural recordings acquired with Intan RHD2000 ICs and tested the repeated performance of 17 ICs in vitro. With the on-chip digital-signal-processing disabled, we detected the ADC artifacts in each test recording by examining the distribution of unfiltered ADC output codes. Main Results: We found larger ADC artifacts in recordings using the Intan RHX data acquisition software versions 3.0-3.2, which did not run the necessary ADC calibration command when the inputs to the Intan recording controller were rescanned. This has been corrected in the Intan RHX software version 3.3. We found that the ADC calibration routine significantly reduced, but did not fully eliminate, the occurrence and size of ADC artifacts as compared with recordings acquired when the calibration routine was not run (p < 0.0001). When the ADC calibration routine was run, we found that the artifacts produced by each ADC were consistent over time, enabling us to sort ICs by performance. Significance: Our findings call attention to the importance of evaluating signal quality when acquiring electrophysiological data using Intan Technologies ICs and offer a method for detecting ADC artifacts in recorded data. .

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.

Materials for multifunctional balloon catheters with capabilities in cardiac electrophysiological mapping and ablation therapy.

Developing advanced surgical tools for minimally invasive procedures represents an activity of central importance to improving human health. A key challenge is in establishing biocompatible interfaces between the classes of semiconductor device and sensor technologies that might be most useful in this context and the soft, curvilinear surfaces of the body. This paper describes a solution based on materials that integrate directly with the thin elastic membranes of otherwise conventional balloon catheters, to provide diverse, multimodal functionality suitable for clinical use. As examples, we present sensors for measuring temperature, flow, tactile, optical and electrophysiological data, together with radiofrequency electrodes for controlled, local ablation of tissue. Use of such 'instrumented' balloon catheters in live animal models illustrates their operation, as well as their specific utility in cardiac ablation therapy. The same concepts can be applied to other substrates of interest, such as surgical gloves.

Data mining neocortical high-frequency oscillations in epilepsy and controls.

Transient high-frequency (100-500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100-250 Hz) and fast ripple (250-500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100-500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.

Proceedings of the Third International Workshop on Advances in Electrocorticography.

The Third International Workshop on Advances in Electrocorticography (ECoG) was convened in Washington, DC, on November 10-11, 2011. As in prior meetings, a true multidisciplinary fusion of clinicians, scientists, and engineers from many disciplines gathered to summarize contemporary experiences in brain surface recordings. The proceedings of this meeting serve as evidence of a very robust and transformative field but will yet again require revision to incorporate the advances that the following year will surely bring.

Design and Simulation of a Low Power 384-channel Actively Multiplexed Neural Interface.

Brain computer interfaces (BCIs) provide clinical benefits including partial restoration of lost motor control, vision, speech, and hearing. A fundamental limitation of existing BCIs is their inability to span several areas (> cm2) of the cortex with fine (<100 µm) resolution. One challenge of scaling neural interfaces is output wiring and connector sizes as each channel must be independently routed out of the brain. Time division multiplexing (TDM) overcomes this by enabling several channels to share the same output wire at the cost of added noise. This work leverages a 130-nm CMOS process and transfer printing to design and simulate a 384-channel actively multiplexed array, which minimizes noise by adding front end filtering and amplification to every electrode site (pixel). The pixels are 50 µm × 50 µm and enable recording of all 384 channels at 30 kHz with a gain of 22.3 dB, noise of 9.57 µV rms, bandwidth of 0.1 Hz - 10 kHz, while only consuming 0.63 µW/channel. This work can be applied broadly across neural interfaces to create high channel-count arrays and ultimately improve BCIs.

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.

Flexural bending to approximate cortical forces exerted by electrocorticography (ECoG) arrays.

Objective.The force that an electrocorticography (ECoG) array exerts on the brain manifests when it bends to match the curvature of the skull and cerebral cortex. This force can negatively impact both short-term and long-term patient outcomes. Here we provide a mechanical characterization of a novel liquid crystal polymer (LCP) ECoG array prototype to demonstrate that its thinner geometry reduces the force potentially applied to the cortex of the brain.Approach.We built a low-force flexural testing machine to measure ECoG array bending forces, calculate their effective flexural moduli, and approximate the maximum force they could exerted on the human brain.Main results.The LCP ECoG prototype was found to have a maximal force less than 20% that of any commercially available ECoG arrays that were tested. However, as a material, LCP was measured to be as much as 24× more rigid than silicone, which is traditionally used in ECoG arrays. This suggests that the lower maximal force resulted from the prototype's thinner profile (2.9×-3.25×).Significance.While decreasing material stiffness can lower the force an ECoG array exhibits, our LCP ECoG array prototype demonstrated that flexible circuit manufacturing techniques can also lower these forces by decreasing ECoG array thickness. Flexural tests of ECoG arrays are necessary to accurately assess these forces, as material properties for polymers and laminates are often scale dependent. As the polymers used are anisotropic, elastic modulus cannot be used to predict ECoG flexural behavior. Accounting for these factors, we used our four-point flexure testing procedure to quantify the forces exerted on the brain by ECoG array bending. With this experimental method, ECoG arrays can be designed to minimize force exerted on the brain, potentially improving both acute and chronic clinical utility.

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.

Electrophysiology and Arrhythmogenesis in the Human Right Ventricular Outflow Tract.

BACKGROUND: Right ventricular outflow tract (RVOT) is a common source of ventricular tachycardia, which often requires ablation. However, the mechanisms underlying the RVOT's unique arrhythmia susceptibility remain poorly understood due to lack of detailed electrophysiological and molecular studies of the human RVOT. METHODS: We conducted optical mapping studies in 16 nondiseased donor human RVOT preparations subjected to pharmacologically induced adrenergic and cholinergic stimulation to evaluate susceptibility to arrhythmias and characterize arrhythmia dynamics. RESULTS: We found that under control conditions, RVOT has shorter action potential duration at 80% repolarization relative to the right ventricular apical region. Treatment with isoproterenol (100 nM) shortened action potential duration at 80% repolarization and increased incidence of premature ventricular contractions (P=0.003), whereas acetylcholine (100 µM) stimulation alone had no effect on action potential duration at 80% repolarization or premature ventricular contractions. However, acetylcholine treatment after isoproterenol stimulation reduced the incidence of premature ventricular contractions (P=0.034) and partially reversed action potential duration at 80% repolarization shortening (P=0.029). Immunolabeling of RVOT (n=4) confirmed the presence of cholinergic marker VAChT (vesicular acetylcholine transporter) in the region. Rapid pacing revealed RVOT susceptibility to both concordant and discordant alternans. Investigation into transmural arrhythmia dynamics showed that arrhythmia wave fronts and phase singularities (rotors) were relatively more organized in the endocardium than in the epicardium (P=0.006). Moreover, there was a weak but positive spatiotemporal autocorrelation between epicardial and endocardial arrhythmic wave fronts and rotors. Transcriptome analysis (n=10 hearts) suggests a trend that MAPK (mitogen-activated protein kinase) signaling, calcium signaling, and cGMP-PKG (protein kinase G) signaling are among the pathways that may be enriched in the male RVOT, whereas pathways of neurodegeneration may be enriched in the female RVOT. CONCLUSIONS: Human RVOT electrophysiology is characterized by shorter action potential duration relative to the right ventricular apical region. Cholinergic right ventricular stimulation attenuates the arrhythmogenic effects of adrenergic stimulation, including increase in frequency of premature ventricular contractions and shortening of wavelength. Right ventricular arrhythmia is characterized by positive spatial-temporal autocorrelation between epicardial-endocardial arrhythmic wave fronts and rotors that are relatively more organized in the endocardium.

Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics.

Electronics that are capable of intimate, non-invasive integration with the soft, curvilinear surfaces of biological tissues offer important opportunities for diagnosing and treating disease and for improving brain/machine interfaces. This article describes a material strategy for a type of bio-interfaced system that relies on ultrathin electronics supported by bioresorbable substrates of silk fibroin. Mounting such devices on tissue and then allowing the silk to dissolve and resorb initiates a spontaneous, conformal wrapping process driven by capillary forces at the biotic/abiotic interface. Specialized mesh designs and ultrathin forms for the electronics ensure minimal stresses on the tissue and highly conformal coverage, even for complex curvilinear surfaces, as confirmed by experimental and theoretical studies. In vivo, neural mapping experiments on feline animal models illustrate one mode of use for this class of technology. These concepts provide new capabilities for implantable and surgical devices.

Proceedings of the Second International Workshop on Advances in Electrocorticography.

The Second International Workshop on Advances in Electrocorticography (ECoG) was convened in San Diego, CA, USA, on November 11-12, 2010. Between this meeting and the inaugural 2009 event, a much clearer picture has been emerging of cortical ECoG physiology and its relationship to local field potentials and single-cell recordings. Innovations in material engineering are advancing the goal of a stable long-term recording interface. Continued evolution of ECoG-driven brain-computer interface technology is determining innovation in neuroprosthetics. Improvements in instrumentation and statistical methodologies continue to elucidate ECoG correlates of normal human function as well as the ictal state. This proceedings document summarizes the current status of this rapidly evolving field.