High-density Electrode Arrays Research Articles

Midbrain responses to micro-stimulation of the cochlea using high density thin-film arrays

A broader activation of auditory nerve fibres than normal using a cochlear implant contributes to poor frequency discrimination. As cochlear implants also deliver a restricted dynamic range, this hinders the ability to segregate sound sources. Better frequency coding and control over amplitude may be achieved by limiting current spread during electrical stimulation of the cochlea and positioning electrodes closer to the modiolus. Thin-film high density microelectrode arrays and conventional platinum ring electrode arrays were used to stimulate the cochlea of urethane-anaesthetized rats and responses compared. Neurophysiological recordings were taken at 197 multi-unit clusters in the central nucleus of the inferior colliculus (CIC), a site that receives direct monaural innervation from the cochlear nucleus. CIC responses to both the platinum ring and high density electrodes were recorded and differences in activity to changes in stimulation intensity, thresholds and frequency coding of neural activation were examined. The high density electrode array elicited less CIC activity at nonspecific frequency regions than the platinum ring electrode array. The high density electrode array produced significantly lower thresholds and larger dynamic ranges than the platinum ring electrode array when positioned close to the modiolus. These results suggest that a higher density of stimulation sites on electrodes that effectively ‘aim’ current, combined with placement closer to the modiolus would permit finer control over charge delivery. This may equate to improved frequency specific perception and control over amplitude when using future cochlear implant devices.

Multiscale functional connectivity estimation on low-density neuronal cultures recorded by high-density CMOS Micro Electrode Arrays

We used electrophysiological signals recorded by CMOS Micro Electrode Arrays (MEAs) at high spatial resolution to estimate the functional-effective connectivity of sparse hippocampal neuronal networks in vitro by applying a cross-correlation (CC) based method and ad hoc developed spatio-temporal filtering. Low-density cultures were recorded by a recently introduced CMOS-MEA device providing simultaneous multi-site acquisition at high-spatial (21μm inter-electrode separation) as well as high-temporal resolution (8kHz per channel). The method is applied to estimate functional connections in different cultures and it is refined by applying spatio-temporal filters that allow pruning of those functional connections not compatible with signal propagation. This approach permits to discriminate between possible causal influence and spurious co-activation, and to obtain detailed maps down to cellular resolution. Further, a thorough analysis of the links strength and time delays (i.e., amplitude and peak position of the CC function) allows characterizing the inferred interconnected networks and supports a possible discrimination of fast mono-synaptic propagations, and slow poly-synaptic pathways. By focusing on specific regions of interest we could observe and analyze microcircuits involving connections among a few cells. Finally, the use of the high-density MEA with low density cultures analyzed with the proposed approach enables to compare the inferred effective links with the network structure obtained by staining procedures.

A novel high electrode count spike recording array using an 81,920 pixel transimpedance amplifier-based imaging chip

Microelectrode recording arrays of 60–100 electrodes are commonly used to record neuronal biopotentials, and these have aided our understanding of brain function, development and pathology. However, higher density microelectrode recording arrays of larger area are needed to study neuronal function over broader brain regions such as in cerebral cortex or hippocampal slices. Here, we present a novel design of a high electrode count picocurrent imaging array (PIA), based on an 81,920 pixel Indigo ISC9809 readout integrated circuit camera chip. While originally developed for interfacing to infrared photodetector arrays, we have adapted the chip for neuron recording by bonding it to microwire glass resulting in an array with an inter-electrode pixel spacing of 30μm. In a high density electrode array, the ability to selectively record neural regions at high speed and with good signal to noise ratio are both functionally important. A critical feature of our PIA is that each pixel contains a dedicated low noise transimpedance amplifier (∼0.32pA rms) which allows recording high signal to noise ratio biocurrents comparable to single electrode voltage amplifier recordings. Using selective sampling of 256 pixel subarray regions, we recorded the extracellular biocurrents of rabbit retinal ganglion cell spikes at sampling rates up to 7.2kHz. Full array local electroretinogram currents could also be recorded at frame rates up to 100Hz. A PIA with a full complement of 4 readout circuits would span 1cm and could acquire simultaneous data from selected regions of 1024 electrodes at sampling rates up to 9.3kHz.

Avalanche Analysis from Multielectrode Ensemble Recordings in Cat, Monkey, and Human Cerebral Cortex during Wakefulness and Sleep

Self-organized critical states are found in many natural systems, from earthquakes to forest fires, they have also been observed in neural systems, particularly, in neuronal cultures. However, the presence of critical states in the awake brain remains controversial. Here, we compared avalanche analyses performed on different in vivo preparations during wakefulness, slow-wave sleep, and REM sleep, using high density electrode arrays in cat motor cortex (96 electrodes), monkey motor cortex and premotor cortex and human temporal cortex (96 electrodes) in epileptic patients. In neuronal avalanches defined from units (up to 160 single units), the size of avalanches never clearly scaled as power-law, but rather scaled exponentially or displayed intermediate scaling. We also analyzed the dynamics of local field potentials (LFPs) and in particular LFP negative peaks (nLFPs) among the different electrodes (up to 96 sites in temporal cortex or up to 128 sites in adjacent motor and premotor cortices). In this case, the avalanches defined from nLFPs displayed power-law scaling in double logarithmic representations, as reported previously in monkey. However, avalanche defined as positive LFP (pLFP) peaks, which are less directly related to neuronal firing, also displayed apparent power-law scaling. Closer examination of this scaling using the more reliable cumulative distribution function (CDF) and other rigorous statistical measures, did not confirm power-law scaling. The same pattern was seen for cats, monkey, and human, as well as for different brain states of wakefulness and sleep. We also tested other alternative distributions. Multiple exponential fitting yielded optimal fits of the avalanche dynamics with bi-exponential distributions. Collectively, these results show no clear evidence for power-law scaling or self-organized critical states in the awake and sleeping brain of mammals, from cat to man.

Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo

Arrays of electrodes for recording and stimulating the brain are used throughout clinical medicine and basic neuroscience research, yet are unable to sample large areas of the brain while maintaining high spatial resolution because of the need to individually wire each passive sensor at the electrode-tissue interface. To overcome this constraint, we have developed new devices integrating ultrathin and flexible silicon nanomembrane transistors into the electrode array, enabling new dense arrays of thousands of amplified and multiplexed sensors connected using many fewer wires. We used this system to record novel spatial properties of brain activity in vivo, including sleep spindles, single-trial visual evoked responses, and electrographic seizures. Our electrode array allowed us to discover that seizures may manifest as recurrent spiral waves which propagate in the neocortex. The developments reported here herald a new generation of diagnostic and therapeutic brain-machine interface (BMI) devices.

Examining the Characteristics of Episodic Memory using Event-related Potentials in Patients with Alzheimer's Disease

Our laboratory uses event-related EEG potentials (ERPs) to understand and support behavioral investigations of episodic memory in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Whereas behavioral data inform us about the patients' performance, ERPs allow us to record discrete changes in brain activity. Further, ERPs can give us insight into the onset, duration, and interaction of independent cognitive processes associated with memory retrieval. In patient populations, these types of studies are used to examine which aspects of memory are impaired and which remain relatively intact compared to a control population. The methodology for collecting ERP data from a vulnerable patient population while these participants perform a recognition memory task is reviewed. This protocol includes participant preparation, quality assurance, data acquisition, and data analysis. In addition to basic setup and acquisition, we will also demonstrate localization techniques to obtain greater spatial resolution and source localization using high-density (128 channel) electrode arrays.

An automated system for rapid evaluation of high-density electrode arrays in neural prostheses

The success of high-density electrode arrays for use in neural prostheses depends on efficient impedance monitoring and fault detection. Conventional methods of impedance testing and fault detection are time consuming and not always suited for in vivo assessment of high-density electrode arrays. Additionally, the ability to evaluate impedances and faults such as open and short circuits, both in vitro and in vivo, are important to ensure safe and effective stimulation. In this work we describe an automated system for the rapid evaluation of high-density electrode arrays. The system uses a current pulse similar to that used to stimulate neural tissue and measures the voltage across the electrode in order to calculate the impedance. The switching of the system was validated by emulating a high-density electrode array using light-emitting diodes and a resistor–capacitor network. The system was tested in vitro and in vivo using a range of commercially available and in-house developed electrode arrays. The system accurately identified faults in an 84-electrode array in less than 20 s and reliably measured impedances up to 110 kΩ using a 200 µA, 250 µs per phase current pulse. This system has direct application for screening high-density electrode arrays in both clinical and experimental settings.

Sub-centimeter language organization in the human temporal lobe

The human temporal lobe is well known to be critical for language comprehension. Previous physiological research has focused mainly on non-invasive neuroimaging and electrophysiological techniques with each approach requiring averaging across many trials and subjects. The results of these studies have implicated extended anatomical regions in peri-sylvian cortex in speech perception. These non-invasive studies typically report a spatially homogenous functional pattern of activity across several centimeters of cortex. We examined the spatiotemporal dynamics of word processing using electrophysiological signals acquired from high-density electrode arrays (4 mm spacing) placed directly on the human temporal lobe. Electrocorticographic (ECoG) activity revealed a rich mosaic of language activity, which was functionally distinct at four mm separation. Cortical sites responding specifically to word and not phoneme stimuli were surrounded by sites that responded to both words and phonemes. Other sub-regions of the temporal lobe responded robustly to self-produced speech and minimally to external stimuli while surrounding sites at 4 mm distance exhibited an inverse pattern of activation. These data provide evidence for temporal lobe specificity to words as well as self-produced speech. Furthermore, the results provide evidence that cortical processing in the temporal lobe is not spatially homogenous over centimeters of cortex. Rather, language processing is supported by independent and spatially distinct functional sub-regions of cortex at a resolution of at least 4 mm.

Patterning of Polymer Electrodes by Nanoscratching

The patterning of conducting polymer PEDOT:PSS, an excellent organic electrode material, with high resolution (50 nm, middle part of figure) on both rigid and flexible substrates by AFM nanoscratching (left part of figure) is demonstrated. The high density electrode array (108 elements cm−2) and small area electrode pair (0.5–0.6 µm2) achieved by this technique demonstrates its excellent patterning ability. The scratched nano/sub-micrometer channel shows excellent performance in organic transistors (right part of figure) with high performance and low voltage.

Quantifying auditory event-related responses in multichannel human intracranial recordings

Multichannel intracranial recordings are used increasingly to study the functional organization of human cortex. Intracranial recordings of event-related activity, or electrocorticography (ECoG), are based on high density electrode arrays implanted directly over cortex, combining good temporal and spatial resolution. Developing appropriate statistical methods for analyzing event-related responses in these high dimensional ECoG datasets remains a major challenge for clinical and systems neuroscience. We present a novel methodological framework that combines complementary, existing methods adapted for statistical analysis of auditory event-related responses in multichannel ECoG recordings. This analytic framework integrates single-channel (time-domain, time–frequency) and multichannel analyses of event-related ECoG activity to determine statistically significant evoked responses, induced spectral responses, and effective (causal) connectivity. Implementation of this quantitative approach is illustrated using multichannel ECoG data from recent studies of auditory processing in patients with epilepsy. Methods described include a time–frequency matching pursuit algorithm adapted for modeling brief, transient cortical spectral responses to sound, and a recently developed method for estimating effective connectivity using multivariate autoregressive modeling to measure brief event-related changes in multichannel functional interactions. A semi-automated spatial normalization method for comparing intracranial electrode locations across patients is also described. The individual methods presented are published and readily accessible. We discuss the benefits of integrating multiple complementary methods in a unified and comprehensive quantitative approach. Methodological considerations in the analysis of multichannel ECoG data, including corrections for multiple comparisons are discussed, as well as remaining challenges in the development of new statistical approaches.

Wireless technologies for closed-loop retinal prostheses

In this paper, we discuss various technologies needed to develop retinal prostheses with wireless power and data telemetry operation. In addition to the need to communicate with the implanted device, supply of power to the retinal prosthesis is especially difficult. This is because, in the implanted state, the device is not fixed in position due to constant motion of the eye. Furthermore, a retinal prosthesis incorporating a high density electrode array of more than 1000 electrodes is expected to consume approximately 45 mW of power and require 300 kbps of image and stimulation data. The front end of the wireless power and data transmission, the antenna, needs to be small compared to the size of the eye. Also, the wireless module is expected to operate in the reactive near-field region due to small separation between the transmit and receive antennas compared to their size and corresponding operating wavelength. An inductive link is studied as a means to transfer power and for data telemetry between the implant and external unit. In this work, the use of integrated circuit and microfabrication technologies for implementing inductive links is discussed. A closed-loop approach is taken to improve performance and reach optimum operation condition. Design and simulation data are presented as the basis for development of viable wireless module prototypes.

Clinical Applications of Intraspinal Microstimulation

Intraspinal microstimulation is a neuroprosthetic approach for activating specific spinal reflexes using penetrating electrodes chronically implanted into spinal cord. Artificial control of spinally mediated functions, such as arm and leg movement or bladder voiding, may be necessary in spinal cord injury, multiple sclerosis, cerebral palsy, amyotrophic lateral sclerosis, and spina bifida, when the brain becomes disconnected from spinal cord and a person loses control over these functions. Animal studies indicate the feasibility of efficient control of bladder voiding and limb movement. Development of novel microstimulation electrodes focuses on reduction of electrode dimensions for improved targeting efficiency, decreased tissue trauma, improved biocompatibility, and long-term safety and reliability of applied stimulation. Clinical usefulness of existing devices is limited by a lack of highly integrated and biocompatible neuroprosthetic systems, comprising high-density electrode arrays and integrated electronics for pulse generation and stimulation site addressing. Future developments will require a coordinated effort in the areas of neural prosthetic engineering, applied neurophysiology, neurosurgery, physical therapy, and rehabilitation. In the long term, clinical applications of intraspinal microstimulation may include treatments of such spinal cord-related disabilities, such as bladder and bowel emptying, sexual function, hand and arm control, and even walking. These treatments can address the long-standing needs of paralyzed patients aimed at improving their medical, psychological, social, and work-related conditions.

High-density cochlear implants with position sensing and control

Silicon-based thin-film technology has been used to develop high-density cochlear electrode arrays with up to 32 sites and four parallel channels of simultaneous stimulation. The lithographically-defined arrays utilize a silicon-dielectric-metal-parylene structure with 180μm-diameter IrO sites on 250 μm centers. Eight on-board strain gauges allow real-time imaging of array shape during insertion, and a tip sensor measures forces on any structures contacted in the scala tympani (e.g., the basilar membrane). The array can be pre-stressed to hug the modiolus, which provides position reference. Tip position can be resolved to better than 50 μm. Circuitry mounted on the base of the array generates stimulating currents, records intra-cochlear responses and position information, and interfaces with a custom microcontroller and inductively-coupled wireless interface over an eight-lead ribbon cable. The circuitry delivers biphasic 500 μA current pulses with 4 μA resolution and a minimum pulse width of 4 μs. Multiple sites can be driven in parallel to provide higher current levels. Backing structures and articulated insertion tools are being developed for dynamic closed-loop insertion control.

Flexible parylene-based multielectrode array technology for high-density neural stimulation and recording

Novel flexible parylene-based high-density electrode arrays have been developed for functional electrical stimulation in retinal and spinal cord prosthetics. These arrays are microfabricated according to a single-metal-layer process and a revolutionary dual-metal-layer process that promises to meet the needs of extremely high-density stimulation applications. While in many cases thin-film platinum electrodes in parylene C would be sufficient, high surface-area platinum electroplating has been shown to extend the lifetime of stimulated electrodes to more than 430 million pulses without failing. Iridium electrode arrays with higher charge delivery capacity have also been fabricated using a new high-temperature stabilized parylene variant, parylene HT. In addition, a new heat molding process has been implemented to conform electrode arrays to approximate the curvature of canine retinas, and a chronic implantation study of the mechanical effects of parylene-based electrode arrays on the retina over a 6-month follow-up period has provided excellent results. Retinal stimulation from these parylene-based electrode arrays in an isolated tiger salamander preparation was shown to be comparable to light stimulation in terms of generation of action potentials in the inner retina. Finally, electrode arrays have also been implanted and tested on the spinal cords of murine models, with the ultimate goal of facilitation of locomotion after spinal cord injury; these arrays provide a higher density and better spatial control of stimulation and recording than is typically possible using traditional fine-wire electrodes. Spinal cord stimulation typically elicited three muscle responses, an early (direct), a middle (monosynaptic), and a late (polysynaptic) response, classified based on latency after stimulation. Stimulation at different rostrocaudal levels of the cord yielded markedly different muscle responses, highlighting the need for such high-density arrays.

Decoding a New Neural–Machine Interface for Control of Artificial Limbs

An analysis of the motor control information content made available with a neural-machine interface (NMI) in four subjects is presented in this study. We have developed a novel NMI-called targeted muscle reinnervation (TMR)-to improve the function of artificial arms for amputees. TMR involves transferring the residual amputated nerves to nonfunctional muscles in amputees. The reinnervated muscles act as biological amplifiers of motor commands in the amputated nerves and the surface electromyogram (EMG) can be used to enhance control of a robotic arm. Although initial clinical success with TMR has been promising, the number of degrees of freedom of the robotic arm that can be controlled has been limited by the number of reinnervated muscle sites. In this study we assess how much control information can be extracted from reinnervated muscles using high-density surface EMG electrode arrays to record surface EMG signals over the reinnervated muscles. We then applied pattern classification techniques to the surface EMG signals. High accuracy was achieved in the classification of 16 intended arm, hand, and finger/thumb movements. Preliminary analyses of the required number of EMG channels and computational demands demonstrate clinical feasibility of these methods. This study indicates that TMR combined with pattern-recognition techniques has the potential to further improve the function of prosthetic limbs. In addition, the results demonstrate that the central motor control system is capable of eliciting complex efferent commands for a missing limb, in the absence of peripheral feedback and without retraining of the pathways involved.

Large-scale multielectrode recording and stimulation of neural activity

Large circuits of neurons are employed by the brain to encode and process information. How this encoding and processing is carried out is one of the central questions in neuroscience. Since individual neurons communicate with each other through electrical signals (action potentials), the recording of neural activity with arrays of extracellular electrodes is uniquely suited for the investigation of this question. Such recordings provide the combination of the best spatial (individual neurons) and temporal (individual action-potentials) resolutions compared to other large-scale imaging methods. Electrical stimulation of neural activity in turn has two very important applications: it enhances our understanding of neural circuits by allowing active interactions with them, and it is a basis for a large variety of neural prosthetic devices. Until recently, the state-of-the-art in neural activity recording systems consisted of several dozen electrodes with inter-electrode spacing ranging from tens to hundreds of microns. Using silicon microstrip detector expertise acquired in the field of high-energy physics, we created a unique neural activity readout and stimulation framework that consists of high-density electrode arrays, multi-channel custom-designed integrated circuits, a data acquisition system, and data-processing software. Using this framework we developed a number of neural readout and stimulation systems: (1) a 512-electrode system for recording the simultaneous activity of as many as hundreds of neurons, (2) a 61-electrode system for electrical stimulation and readout of neural activity in retinas and brain-tissue slices, and (3) a system with telemetry capabilities for recording neural activity in the intact brain of awake, naturally behaving animals. We will report on these systems, their various applications to the field of neurobiology, and novel scientific results obtained with some of them. We will also outline future directions.

Resting State Cortical Connectivity Reflected in EEG Coherence in Individuals With Autism

Theoretical conceptions of autism spectrum disorder (ASD) and experimental studies of cerebral blood flow suggest abnormalities in connections among distributed neural systems in ASD. Functional connectivity was assessed with electroencephalographic coherence between pairs of electrodes in a high-density electrode array in narrow frequency bands among 18 adults with ASD and 18 control adults in an eyes closed resting state. In the theta (3-6 Hz) frequency range, locally elevated coherence was evident for the ASD group, especially within left hemisphere frontal and temporal regions. In the lower alpha range (8-10 Hz), globally reduced coherence was evident for the ASD group within frontal regions and between frontal and all other scalp regions. The ASD group exhibited significantly greater relative power between 3 and 6 Hz and 13-17 Hz and significantly less relative power between 9 and 10 Hz. Robust patterns of over- and under-connectivity are apparent at distinct spatial and temporal scales in ASD subjects in the eyes closed resting state.

A 32-Site 4-Channel High-Density Electrode Array for a Cochlear Prosthesis

This paper describes a 32-site 4-channel high-density intracochlear electrode array. Combining MEMS-based processing technology with active circuitry, the thin-film device realizes a stimulating site density three times that of commercial systems, delivering 500 muA biphasic current levels with 8-bit resolution and less than 1% charge mismatch. The minimum pulsewidth is 4 mus, and the per-channel power dissipation is 2.5 mW from plusmn2.5 V. The active circuit chip has a footprint of 2.4mmtimes2.9 mm. Serving as the end-effector of a cochlear prosthesis, the active array also provides site-impedance measurement and position-sensing functions

Scalable high lead-count parylene package for retinal prostheses

We present the first packaging technology for high lead-count retinal prostheses capable of fully scalable interconnection of a high-density electrode array, a radiofrequency (RF) telemetry coil, and other discrete components, such as chip capacitors, with prefabricated, stand-alone driver circuitry. This parylene-based drop-chip technology enables the application-specific integrated circuit (ASIC) to be directly integrated into the fabrication process of the other system components, such that the resulting device is flexible, facilitating surgical implantation. The ASIC-to-electrode interconnects are patterned using standard photolithography and standard microfabrication techniques, enabling the density of interconnects to scale to the limits of the lithographic equipment used to define the etch holes over the on-chip pads. This scheme also enables the simultaneous integration and interconnection of multiple ASICs with the rest of the system in such a way that the best features of chip-level and wafer-level packaging technologies are combined into a single process. Using this technique, standard photolithography and interconnect fabrication has been performed successfully on 10 chips. Electrical test results verify the efficacy of this cost-effective and high-yield packaging scheme, and pave the way for a monolithic implantable parylene-based retinal prosthesis system as well as other systems requiring the capability to perform microfabrication steps on prefabricated chips.

Microelectronic packaging for retinal prostheses

An innovative parylene-based high-density chip-level integrated interconnect (CL-I/sup 2/) packaging system for retinal implants id discussed. The implications of this CL-I/sup 2/ technology for retinal prosthesis packaging effort are far-reaching. This technology obviates the need for a technician to create electrical and mechanical connections one by one. Instead, the technology is limited only by standard photolithography and standard microfabrication techniques, providing the capability for a reduction of an order of magnitude or more in the center-to-center pad distances that can be accommodated in the process. High-density electrode arrays are thereby feasible, because the fabrication process places no limit on the number of output pads that can reasonably be connected to the array.