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Goal: Develop and characterize the functionality of a novel thin-film probe technology with a higher density of electrode contacts than are currently available with commercial deep brain stimulation (DBS) lead technology. Such technology has potential to enhance the spatial precision of DBS and enable a more robust approach to sensing local field potential activity in the context of adaptive DBS strategies. Methods: Thin-film planar arrays were microfabricated and then assembled on a cylindrical carrier to achieve a lead with 3-D conformation. Using an integrated and removable stylet, the arrays were chronically implanted in the subthalamic nucleus and globus pallidus in two parkinsonian nonhuman primates. Results: This study provides the first in vivo data from chronically implanted DBS arrays for translational nonhuman primate studies. Stimulation through the arrays induced a decrease in parkinsonian rigidity, and directing current around the lead showed an orientation dependence for eliciting motor capsule side effects. The array recordings also showed that oscillatory activity in the basal ganglia is heterogeneous at a smaller scale than detected by the current DBS lead technology. Conclusion: These 3-D DBS arrays provide an enabling tool for future studies that seek to monitor and modulate deep brain activity through chronically implanted leads. Significance: DBS lead technology with a higher density of electrode contacts has potential to enable sculpting DBS current flow and sensing biomarkers of disease and therapy.

To understand how function arises from the interactions between neurons, it is necessary to use methods that allow the monitoring of brain activity at the single-neuron, single-spike level and the targeted manipulation of the diverse neuron types selectively in a closed-loop manner. Large-scale recordings of neuronal spiking combined with optogenetic perturbation of identified individual neurons has emerged as a suitable method for such tasks in behaving animals. To fully exploit the potential power of these methods, multiple steps of technical innovation are needed. We highlight the current state of the art in electrophysiological recording methods, combined with optogenetics, and discuss directions for progress. In addition, we point to areas where rapid development is in progress and discuss topics where near-term improvements are possible and needed.

Successfully and efficiently bridging peripheral nerve gaps without the use of autografts is a substantial clinical advance for peripheral nerve reconstructions. Novel templating methods for the fabrication of conductive hydrogel guidance channels for axonal regeneration are designed and developed. PEDOT is electrodeposited inside the lumen to create fully coated-PEDOT agarose conduits and partially coated-PEDOT agarose conduits.

The authors' goal is to develop a peripheral nerve electrode with long-term stability and fidelity for use in nerve/machine interfaces. Microelectromechanical systems use silicon probes that contain multichannel actuators, sensors, and electronics. The authors tested the null hypothesis that implantation of microelectromechanical systems probes does not have a detrimental effect on peripheral nerve function or regeneration.A rat hind-limb, peroneal nerve model was used in all experimental groups: intact nerve (control group, n=10); nerve division and repair (repair group, n=9); and nerve division, insertion of microelectromechanical systems probe, and repair (repair plus probe group, n=9). Nerve morphology, nerve to compound muscle action potential studies, walking tracks, and extensor digitorum longus muscle function tests were evaluated following an 80-day recovery.Repair and repair plus probe showed no differences in axon count, axon size, percentage nonneural area, compound muscle action potential amplitude, latency, muscle mass, muscle force, or walking track scores. Although there was some local fibrosis around each microelectromechanical systems probe, this did not lead to measurable detrimental effects in any anatomical or functional outcome measurements.The absence of a significant difference between the repair and the repair plus probe groups regarding histology, compound muscle action potential, walking tracks, and muscle force suggests that microelectromechanical systems electrodes are compatible with regenerating axons and show promise for establishing chemical and electrical interfaces with peripheral nerves.

Objective To investigate steering the volume of activated tissue ( VTA ) with deep brain stimulation (DBS) using a novel high spatial-resolution lead design. Methods We examined the effect of asymmetric current-injection across the DBS-array on the VTA . These predictions were then evaluated acutely in a non-human primate implanted with the DBS-array, using motor side-effect thresholds as the metric for estimating VTA asymmetries. Results Simulations show the DBS-array, with electrodes arranged together in a cylindrical configuration, can generate field distributions equivalent to commercial DBS leads, and these field distributions can be modulated using field-steering methods. Stimulation with implanted DBS-arrays showed directionally-selective muscle activation, presumably through spread of stimulation fields into portions of the corticospinal tract lying in the internal capsule. Conclusions Our computational and experimental studies demonstrate that the DBS-array is capable of spatially selective stimulation. Displacing VTA s away from the lead’s axis can be achieved using a single simple and intuitive control parameter. Significance Optimal DBS likely requires non-uniform VTA s that may differentially affect a nucleus or fiber pathway. The DBS-array allows positioning VTA s with sub-millimeter precision, which is especially relevant for those patients with DBS leads placed in sub-optimal locations. This may present clinicians with an additional degree of freedom to optimize the DBS therapy.

With the emerging interest in local field potentials (LFPs) as input signals for brain-machine interfaces, there is a need for integrated circuits capable of amplifying spikes and LFPs. A two-stage complementary metal-oxide semiconductor (CMOS) amplifier-filter has been implemented with 0.18-μm CMOS for simultaneous, multimodal recording of extracellular unit spikes and LFPs. For the frequency tuning and the reduction of the 1/f noise, it employs a switched-capacitor technique. The filter bandwidth is reconfigurable by using a different sampling clock frequency. The prototype amplifier has gains of 19.1 dB and 37.5 dB for low-pass only filter and cascaded filter, respectively. With a 100-kHz sampling frequency, the equivalent input noise spectral density is 38.8 nV/√Hz while the total power consumption is 69 μW with a 1.6-V supply, including clock generation and biasing occupying an area of 44 × 148 μm(2).

This paper describes a neurostimulation IC for use in advanced closed-loop neurostimulation applications, such as deep brain stimulation (DBS) for treatment and research of neurological disorders including Parkinson's disease. This system senses and filters neural activity with eight pre-amplifiers, a 200 kS/s 8-bit log ADC and digital filters and incorporates 64 programmable current-stimulation channels. The entire device, implemented in 0.18 μm CMOS, occupies 2.7 mm2 and consumes 89 μW in normal operation mode and 271 μW in configuration mode from a 1.8 V supply.

An in vitro comparison of conducting-polymer nanotubes of poly(3,4-ethylenedioxythiophene) (PEDOT) and poly(pyrrole) (PPy) and to their film counterparts is reported. Impedance, charge-capacity density (CCD), tendency towards delamination, and neurite outgrowth are compared. For the same deposition charge density, PPy films and nanotubes grow relatively faster vertically, while PEDOT films and nanotubes grow more laterally. For the same deposition charge density (1.44 C cm(-2)), PPy nanotubes and PEDOT nanotubes have lower impedance (19.5 +/- 2.1 kOmega for PPy nanotubes and 2.5 +/- 1.4 kOmega for PEDOT nanotubes at 1 kHz) and higher CCD (184 +/- 5.3 mC cm(-2) for PPy nanotubes and 392 +/- 6.2 mC cm(-2) for PEDOT nanotubes) compared to their film counterparts. However, PEDOT nanotubes decrease the impedance of neural-electrode sites by about two orders of magnitude (bare iridium 468.8 +/- 13.3 kOmega at 1 kHz) and increase capacity of charge density by about three orders of magnitude (bare iridium 0.1 +/- 0.5 mC cm(-2)). During cyclic voltammetry measurements, both PPy and PEDOT nanotubes remain adherent on the surface of the silicon dioxide while PPy and PEDOT films delaminate. In experiments of primary neurons with conducting-polymer nanotubes, cultured dorsal root ganglion explants remain more intact and exhibit longer neurites (1400 +/- 95 microm for PPy nanotubes and 2100 +/- 150 microm for PEDOT nanotubes) than their film counterparts. These findings suggest that conducting-polymer nanotubes may improve the long-term function of neural microelectrodes.

Recently, a significant amount of effort has been dedicated to understanding factors that influence the functionality of bio-electronic sensors and to development of novel coating technologies for modifying biosensor surfaces. Due to its well-known biocompatibility, alginate hydrogel (HG) has been used as a coating material on neural electrodes for promoting intimate cellular integration, providing a scaffold for local drug delivery, and creating a mechanical buffer between hard electrodes and the soft tissues of the central nervous system. However, neural signal recordings using HG-coated electrodes in animal models are still poorly evaluated. Here, we investigated the effect of the proximity of source neurons around the electrode sites using HG coatings with various thicknesses deposited on microfabricated electrodes, implanted in auditory cortex of guinea pigs. We also evaluated the role of the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) in improving the recording functionality of the HG-coated neural electrodes. A significant loss in recording functionality was observed with thicker HG coatings, as determined by the number of clearly detectable units (30% with 80 microm thick coatings) and average signal-to-noise ratios (3.91 with 80 microm thick coatings). However, deposition of the conducting polymer PEDOT on the electrode sites restored the lost functionality of the electrodes caused by the HG coatings (30 microm). These conducting polymer/HG coatings have the potential to improve long-term performance of the neural electrodes not only by improving the electrode biocompatibility but also by facilitating more efficient signal transmission.

Development of advanced chronic, high-fidelity neural interfaces is accelerating research into brain function[1] and more effective treatments for neurological conditions.[2–5] The primary functional requirements of these interfaces include recording and/or stimulating from a number of discretely sampled volumes of the brain at requisite spatial resolutions for specific time periods that may extend from hours to years.[6–9] This translates to a push towards smaller electrodes that are more biologically transparent and biocompatible[10–12] with a high density of electrode sites that remain functional for long period of time.[13–15] As electrode size goes to the microscale (higher spatial selectivity), the impedance of electrode site increases, and consequently, the quality of signal recordings decreases (lower sensitivity). Thus, there is a trade off between the size (spatial selectivity) and quality of signal recordings (sensitivity) in neural microelectrodes.[16–18] Studies have also shown that the response of brain tissue to implanted microelectrodes includes an acute injury and a chronic reactive tissue response. The chronic response is characterized by the presence of both activated microglia and reactive astrocytes, which eventually encapsulate the electrode to some degree.[10,12,19–21] Consequently, in addition to the initial high impedance of microelectrodes, these reactive tissue responses have been associated with a progressive increase in the impedance of the electrode/tissue interface.[10,12] Therefore, achieving a very low impedance electrode/tissue interface is important for maintaining and improving signal quality.

Parylene-C (poly-chloro-p-xylylene) is an appropriate material for use in an implantable, microfabricated device. It is hydrophobic, conformally deposited, has a low dielectric constant, and superb biocompatibility. Yet for many bioelectrical applications, its poor wet adhesion may be an impassable shortcoming. This research contrasts parylene-C and poly(p-xylylene) functionalized with reactive group X (PPX-X) layers using long-term electrical soak and adhesion tests. The reactive parylene was made of complementary derivatives having aldehyde and aminomethyl side groups (PPX-CHO and PPX-CH2NH2 respectively). These functional groups have previously been shown to covalently react together after heating. Electrical testing was conducted in saline at 37 °C on interdigitated electrodes with either parylene-C or reactive parylene as the metal layer interface. Results showed that reactive parylene devices maintained the highest impedance. Heat-treated PPX-X device impedance was 800% greater at 10 kHz and 70% greater at 1 Hz relative to heated parylene-C controls after 60 days. Heat treatment proved to be critical for maintaining high impedance of both parylene-C and the reactive parylene. Adhesion measurements showed improved wet metal adhesion for PPX-X, which corresponds well with its excellent high frequency performance.

A series of animal experiments was conducted to characterize changes in the complex impedance of chronically implanted electrodes in neural tissue. Consistent trends in impedance changes were observed across all animals, characterized as a general increase in the measured impedance magnitude at 1 kHz. Impedance changes reach a peak approximately 7 days post-implant. Reactive responses around individual electrodes were described using immuno- and histo-chemistry and confocal microscopy. These observations were compared to measured impedance changes. Several features of impedance changes were able to differentiate between confined and extensive histological reactions. In general, impedance magnitude at 1 kHz was significantly increased in extensive reactions, starting about 4 days post-implant. Electrodes with extensive reactions also displayed impedance spectra with a characteristic change at high frequencies. This change was manifested in the formation of a semi-circular arc in the Nyquist space, suggestive of increased cellular density in close proximity to the electrode site. These results suggest that changes in impedance spectra are directly influenced by cellular distributions around implanted electrodes over time and that impedance measurements may provide an online assessment of cellular reactions to implanted devices.

Insertion trauma is a critical issue when assessing intracortical electrophysiological and neurochemical recordings. Previous reports document a wide variety of insertion techniques with speeds ranging from 10 microm/s to 10 m/s. We hypothesize that insertion speed has an effect on tissue trauma induced by implantation of a neural probe. In order to monitor the neural interface during and after probe insertion, we have developed a silicon-substrate array with hydrous iridium oxide microelectrodes for potentiometric recording of extracellular pH (pH(e)), a measure of brain homeostasis. Microelectrode sites were sensitive to pH in the super-Nernstian range (-85.9 mV/pH unit) and selective over other analytes including ascorbic acid, Na(+), K(+), Ca(2+), and Mg(2+). Following insertion, arrays recorded either triphasic or biphasic pH(e) responses, with a greater degree of prolonged acidosis for insertions at 50 microm/s than at 0.5 mm/s or 1.0 mm/s (p

Recent neuroprosthetic work has focused on the motor cortex as a source of voluntary control signals. However, the motor cortex can be damaged in upper motor neuron degenerative diseases such as primary lateral sclerosis and amyotrophic lateral sclerosis. The possibility exists that prefrontal areas may also be used in neuroprosthetic devices. Here, we report the use of the cingulate cortex in a neuroprosthetic model. Seven rats were able to significantly modulate spiking activity in the cingulate cortex in order to receive reward. Furthermore, experiments with single neurons provide evidence that the cingulate cortex neuronal modulation is highly flexible and thus useful for a neuroprosthetic device.

Current neuroprosthetic systems based on electrophysiological recording have an extended, yet finite working lifetime. Some posited lifetime-extension solutions involve improving device biocompatibility or suppressing host immune responses. Our objective was to test an alternative solution comprised of applying a voltage pulse to a microelectrode site, herein termed "rejuvenation." Previously, investigators have reported preliminary electrophysiological results by utilizing a similar voltage pulse. In this study we sought to further explore this phenomenon via two methods: 1) electrophysiology; 2) an equivalent circuit model applied to impedance spectroscopy data. The experiments were conducted via chronically implanted silicon-substrate iridium microelectrode arrays in the rat cortex. Rejuvenation voltages resulted in increased unit recording signal-to-noise ratios (10%/spl plusmn/2%), with a maximal increase of 195% from 3.74 to 11.02. Rejuvenation also reduced the electrode site impedances at 1 kHz (67%/spl plusmn/2%). Neither the impedance nor recording properties of the electrodes changed on neighboring microelectrode sites that were not rejuvenated. In the equivalent circuit model, we found a transient increase in conductivity, the majority of which corresponded to a decrease in the tissue resistance component (44%/spl plusmn/7%). These findings suggest that rejuvenation may be an intervention strategy to prolong the functional lifetime of chronically implanted microelectrodes.

Sensory cortical prostheses have potential to aid people suffering from blindness, deafness and other sensory deficits. However, research to date has shown that sensation thresholds via epicortical stimulation are surprisingly large. These thresholds result in potentially deleterious electrical currents, as well as large activation volumes. Large activation volumes putatively limit the corresponding number of independent stimulation channels in a neural prosthesis. In this study, penetrating stimulation of the auditory cortex was tested for its ability to transmit salient information to behaving rat subjects. Here, we show that subjects that were previously trained to discriminate natural stimuli immediately discriminated different microstimulation cues more accurately and with shorter response latencies than the natural stimuli. Additionally, the cortical microstimulation resulted in a generalization gradient across locations within the cortex. The results demonstrate the efficacy of using closely spaced cortical microstimulation to efficiently transmit highly salient and discriminable information to a behaving subject.

Methods are presented to incorporate polymer-based bioactive matrices into micro-fabricated implantable microelectrode arrays. Using simple techniques, hydrogels infused with bioactive molecules are deposited within wells in the substrate of the device. This method allows local drug delivery without increasing the footprint of the device. In addition, each well can be loaded individually, allowing spatial and temporal control over diffusion gradients in the microenvironment of the implanted neural interface probe. In vivo testing verified the following: diffusion of the bioactive molecules, integration of the bioactive molecules with the intended neural target and concurrent extracellular recording using nearby electrodes. These results support the feasibility of using polymer gels to deliver bioactive molecules to the region close to microelectrode shanks. This technique for microdrug delivery may serve as a means to intervene with the initial phases of the neuroinflammatory tissue response to permanently implanted microelectrode arrays.

Reactive tissue encapsulation of chronically implanted microelectrode probes can preclude long-term recording of extracellular action potentials. We investigated an intervention strategy for functionally encapsulated microelectrode sites. This method, known as "rejuvenation," involved applying a +1.5 V dc bias to an iridium site for 4 s. Previous studies have demonstrated that rejuvenation resulted in higher signal-to-noise ratios (SNRs) by decreasing noise levels, and reduced 1-kHz site impedances by decreasing the tissue interface resistances. In this study, we have investigated: 1) the duration of a single-voltage bias session and 2) the efficacy of multiple sessions. These questions were addressed through electrophysiological recordings, cyclic voltammetry, and modeling the electrode-tissue interface via an equivalent circuit model fit to impedance spectroscopy data. In the six implants studied, we found SNRs improved for 1-7 days with a peak typically occurring within 24 h of the voltage bias. Root-mean square (RMS) noise of the extracellular recordings decreased for 1-2 days, which paralleled a similar decrease in the adsorbed tissue resistance (R/sub en/) from the model. Implants whose SNR effects lasted more than a day showed stabilized reductions in the extracellular tissue resistance (R/sub ex/) and cellular membrane area (A/sub m/). Subsequent stimulus sessions were found to drop neural tissue parameters consistently to levels observed immediately after surgery. In most cases, these changes did parallel an improvement in SNR. These findings suggest that rejuvenation may be a useful intervention strategy to prolong the lifetime of chronically implanted microelectrodes.

The ability to control a prosthetic device directly from the neocortex has been demonstrated in rats, monkeys and humans. Here we investigate whether neural control can be accomplished in situations where (1) subjects have not received prior motor training to control the device (naive user) and (2) the neural encoding of movement parameters in the cortex is unknown to the prosthetic device (naive controller). By adopting a decoding strategy that identifies and focuses on units whose firing rate properties are best suited for control, we show that naive subjects mutually adapt to learn control of a neural prosthetic system. Six untrained Long-Evans rats, implanted with silicon micro-electrodes in the motor cortex, learned cortical control of an auditory device without prior motor characterization of the recorded neural ensemble. Single- and multi-unit activities were decoded using a Kalman filter to represent an audio "cursor" (90 ms tone pips ranging from 250 Hz to 16 kHz) which subjects controlled to match a given target frequency. After each trial, a novel adaptive algorithm trained the decoding filter based on correlations of the firing patterns with expected cursor movement. Each behavioral session consisted of 100 trials and began with randomized decoding weights. Within 7 +/- 1.4 (mean +/- SD) sessions, all subjects were able to significantly score above chance (P0.05, randomization method) in a fixed target paradigm. Training lasted 24 sessions in which both the behavioral performance and signal to noise ratio of the peri-event histograms increased significantly (P0.01, ANOVA). Two rats continued training on a more complex task using a bilateral, two-target control paradigm. Both subjects were able to significantly discriminate the target tones (P0.05, Z-test), while one subject demonstrated control above chance (P0.05, Z-test) after 12 sessions and continued improvement with many sessions achieving over 90% correct targets. Dynamic analysis of binary trial responses indicated that early learning for this subject occurred during session 6. This study demonstrates that subjects can learn to generate neural control signals that are well suited for use with external devices without prior experience or training.

To better understand the nature and time course for learning-induced cortical reorganization, we examined frequency-specific changes in auditory cortex as cats gradually improved at a difficult sound frequency discrimination task. Three adult cats were trained to discriminate between a tone pip at a fixed target frequency (S−) and a higher deviant frequency (S+). An adaptive training schedule led to an efficient estimate of the frequency discrimination threshold (FDT), which was used to track daily performance. Each cat was also implanted with an array of microwires in auditory cortex. Tone pips with different frequency and amplitude were used to map receptive fields. Onset responses were correlated with training time and the cat's ability to discriminate frequencies. Although lifetime of the neural implants varied among cats, each provided sufficient neural recording to relate at least 3 weeks of learning to response changes in the cortex. An improved FDT was associated with a differential decrease in response strength between the S− frequency and S+ frequencies. Response to the training frequencies gradually located in a local minimum compared to adjacent frequencies (p < 0.001, Cohen's d=0.50). Cortical changes were consistent with a theory of bimodal generalization that enhances stimulus classification by reducing similarity between reinforced and nonreinforced stimuli. Such a strategy may be especially appropriate during an early stage of learning to discriminate similar sounds and differ from later strategies required for fine discrimination.

OBJECTIVE: We sought to expand our assessment of calcium alginate as an embolic agent in an animal model of a cerebral arteriovenous malformation (AVM). The objective of this study was to assess the long-term biocompatibility and stability of calcium alginate in AVM swine models that survived from 1 to 6 months. METHODS: The swine model included a carotid-jugular anastomosis to redirect flow to the rete mirabile (RM), thereby simulating flow to an AVM. Alginate and the reactive component, calcium chloride, were injected from double-lumen or concentric-tube microcatheters to form an occlusion of the RM feeding vessel and the inferior portion of the RM. RESULTS: Angiography and histology verified complete occlusion of the RM feeding vessel for up to 6 months in eight of nine swine. Blood flow remained open to the superior portion of the RM and the circle of Willis. No evidence of downstream calcium alginate gel was seen in the follow-up angiograms or the histological preparations of the circle of Willis. A minor bioactive response to the alginate gel was noted at 1 month, yet no degenerative or inflammatory response was seen. At 6 months, there was moderate fibrous tissue around the alginate, which further sealed off flow to the embolized areas of the RM. CONCLUSION: Over a period of 6 months, calcium alginate was an effective endovascular occlusion material that blocked blood flow to the inferior portion of the RM. The chronic AVM model verified the long-term stability and biocompatibility of calcium alginate.

An important aspect of the development of cortical prostheses is the enhancement of suitable implantable microelectrode arrays for chronic neural recording. The objective of this study was to investigate the recording performance of silicon-substrate micromachined probes in terms of reliability and signal quality. These probes were found to consistently and reliably provide high-quality spike recordings over extended periods of time lasting up to 127 days. In a consecutive series of ten rodents involving 14 implanted probes, 13/14 (93%) of the devices remained functional throughout the assessment period. More than 90% of the probe sites consistently recorded spike activity with signal-to-noise ratios sufficient for amplitudes and waveform-based discrimination. Histological analysis of the tissue surrounding the probes generally indicated the development of a stable interface sufficient for sustained electrical contact. The results of this study demonstrate that these planar silicon probes are suitable for long-term recording in the cerebral cortex and provide an effective platform technology foundation for microscale intracortical neural interfaces for use in humans.

This paper describes the development of a high-density electronic interface to the central nervous system. Silicon micromachined electrode arrays now permit the long-term monitoring of neural activity in vivo as well as the insertion of electronic signals into neural networks at the cellular level. Efforts to understand and engineer the biology of the implant/tissue interface are also underway. These electrode arrays are facilitating significant advances in our understanding of the nervous system, and merged with on-chip circuitry, signal processing, microfluidics, and wireless interfaces, they are forming the basis for a family of neural prostheses for the possible treatment of disorders such as blindness, deafness, paralysis, severe epilepsy, and Parkinson's disease.

This study investigated the use of planar, silicon-substrate microelectrodes for chronic unit recording in the cerebral cortex. The 16-channel microelectrodes consisted of four penetrating shanks with four recording sites on each shank. The chronic electrode assembly included an integrated silicon ribbon cable and percutaneous connector. In a consecutive series of six rats, 5/6 (83%) of the implanted microelectrodes recorded neuronal spike activity for more than six weeks, with four of the implants (66%) remaining functional for more than 28 weeks. In each animal, more than 80% of the electrode sites recorded spike activity over sequential recording sessions during the postoperative time period. These results provide a performance baseline to support further electrode system development for intracortical neural implant systems for medical applications.

Objective We sought to assess the stability of calcium alginate as an embolic agent in an animal model of a cerebral arteriovenous malformation (AVM). Swine cerebral AVM models were used to test the injectability, radiographic visualization, mechanical stability, and biocompatibility of calcium alginate as an occlusive agent. Methods The swine cerebral AVM model included a carotid-to-jugular anastomosis to increase flow to the rete mirabile (RM), thereby simulating the pressure gradient and shunted blood flow of an AVM. Alginate and the reactive component, calcium chloride, were injected from double-lumen microcatheters to form a complete RM occlusion in the "acute swine" AVM model and a partial occlusion in a "survival swine" model. Results Angiographic and histological results verified complete occlusion of the left RM in acute animals when alginate was injected in stages. Partial RM occlusion in the survival animals blocked blood flow to the inferior portion of the RM but left flow open to the superior portion of the RM and the circle of Willis. One-week survival results showed that the alginate remained a stable occlusive material. Histological results showed a minor bioactive response and encapsulation of the alginate polymer, thereby increasing the stability and effective occlusion of the embolization material. Conclusion Calcium alginate proved to be an effective endovascular occlusion material that blocked blood flow to the swine RM. The swine AVM models provided assessment of alginate injectability and effective occlusion and provided initial in vivo characteristics of alginate stability and biocompatibility.

Previous studies have demonstrated a correlation between cochlear implant recipients' comfort levels (C level, upper limit of dynamic range of stimulation) and the contralateral electrical stapedius reflex (ESR) threshold, detected by acoustic impedance change. However, the utility of the approach is limited because many recipients have no detectable impedance change. The goals of this study were to investigate the utility of the stapedial electromyogram (EMG) for estimating onset and strength of the ESR. Ketamine-anesthetized guinea pigs were implanted with Nucleus electrode arrays and stimulated with biphasic current pulse trains (250 pps) via a Cochlear Corporation CI24M stimulator. Typical EMG recordings (obtained with bipolar microwire electrodes) contained easily detectable unit potentials up to 300 microV in amplitude. Growth response curves (obtained from threshold-crossing counts or rms of the EMG signal) were typically monotonic with dynamic ranges spanning 700 microA or 8 dB. Based on adaptation and temporal properties, the stimulus protocol (500 ms duration with 4-5 s interstimulus intervals) was adequate for producing independent responses. The data presented are consistent with ESR characteristics (acoustic impedance technique) of cochlear implant recipients and with EMG properties of acoustically stimulated guinea pigs. Use of the EMG for characterizing the ESR may eventually be applied to human cochlear implant recipients as a guide in setting the upper limit of the dynamic range.

The development and optimization of calcium alginate for potential use in endovascular occlusion was investigated by testing its in vitro and in vivo mechanical stability and biocompatibility. The compressive resistance, rheology, and polymer yield of reacted alginate, and the polymer viscosity of unreacted alginate, were assessed. Biocompatibility was tested by injecting calcium alginate into the kidney capsule of rats. The reactivity of alginates with various structures and levels of purity were compared visually and histologically. Results suggest that calcium alginate is a biocompatible and mechanically stable gel for endovascular applications. Purified alginates exhibited compressive strength of 22 kPa and above at 40% compression, with no significant loss in elasticity. Purified alginate strength was significantly higher than that of crude alginates (p < 0.08). Purified alginates also exhibited significantly lower tissue reaction than crude alginates (p < 0.05). Of the alginates tested, purified high guluronic acid alginates (PHG) exhibited optimal strength and polymer yield, increased biocompatibility, and decreased viscosity. Clinical embolization treatments may be improved with the development of stable and biocompatible polymers such as calcium alginate. Possible uses of improved endovascular polymers include treating arteriovenous malformations (AVMs), aneurysms, blood flow to tumors, and vascular hemorrhaging.

Chronic multichannel neural recording has emerged as a powerful technique for studying dynamic brain function. In many experimental paradigms, it is important that the same neurons be recorded from day to day. The objective of this study was to develop methods for tracking the recorded neural population over time through analysis of unit waveforms, principle component clusters and response properties of single units and multiunit clusters. We demonstrate that these techniques can be used to provide a useful measure of unit stability over extended recording periods.

Chronic, multichannel recordings provide a method for reliable detection and determination of long-term dynamic functional connectivity. Using chronically implanted multichannel electrode arrays, we simultaneously recorded 30–70 units in guinea pig auditory cortex in daily recording sessions for implant durations of six months. We examined stimulus response properties and correlation strengths in neuron pairs in four animals. Preliminary results from these `snapshots’ of functional connectivity suggest sparse functional connections among widely distributed neurons. Some of these functional connections were found to persist for several days. These results provide a framework upon which further investigations of functional dynamic connectivity can be developed.

We implanted microelectrode arrays bilaterally into auditory cortex of trained cats in order to assess dynamic cortical reorganization. Cats were trained to listen to a series of tone-pip pairs and respond to the pair that had different frequencies. Over several months of training, a gradual decrease (−4.2×10−4 Weber Fractions/training day) in the frequency discrimination threshold occurred (p

Octopus cells of the posteroventral cochlear nucleus precisely fire at the onset of short-duration tone bursts, followed by little sustained activity. While this characteristic onset response has been described in experimental studies, its underlying mechanisms are not completely known. The objective of this study was to investigate these mechanisms through a sensitivity analysis of selected parameters of a compartmental model of the octopus cell. The parameters relate to cell morphology, passive electrical properties, synaptic inputs, and active channels. The modeled responses were used to evaluate the effects of four postulated mechanisms on the onset response: the cell’s small membrane time constant, the cell’s numerous weakly effective excitatory inputs, increases in spike threshold caused by sustained depolarization, and electrical loading of the soma by the dendrites. Simulations indicate that the model’s onset response to tone bursts is an emergent property of multiple cell parameters that is best predicted by the ratio of synaptic conductance density to membrane leakage conductance density and by the level of sustained depolarization during the tone burst.

Cochlear nucleus octopus cells are characterized by a temporally precise response at the onset of tone bursts and other phasic stimuli. The objectives of this study were to develop a biologically plausible model of an octopus cell based on typical morphological and physiological properties, and to describe the model’s ability to simulate responses of octopus cells and onset units. The compartmental model represents the basic morphology of octopus cells with a single passive, equivalent dendrite and a lumped, active soma. Independent, excitatory synaptic inputs are distributed on the dendrite and soma to represent inputs from 60 or 120 auditory-nerve fibers. The computed model responses were evaluated using simulated current injections, short-duration tone bursts, and several other types of stimuli. With biologically plausible values for the model parameters, the representation of 60 auditory-nerve inputs yields responses consistent with an OL unit while the representation of 120 inputs yields responses co...

It has been hypothesized that propriospinal neurons (PNs) in the C3-C4 spinal cord mediates cortical motor commands to the peripheral muscles during tremor in patients with Parkinson's disease (PD). However, there has been no direct evidence so far to support the role of PN in transmitting tremor commands. In this paper, we report the positive correlation of cutaneous afferents with reduction in tremor amplitude and frequency in PD patients. Resting tremor and EMGs of biceps, triceps, flexor digitorum superficialis (FDS), extensor digitorum (ED), flexor carpi ulnaris (FCU) and extensor carpi radialis (ECR) muscles were recorded while transcutaneous electrical stimulation (TES) was applied to the dorsal hand skin of PD subjects. We observed instant suppression of tremor amplitude and EMGs occurring immediately at the start of electrical stimulation. However at the end of stimulation, the tremor amplitude and EMGs showed a quick recovery to the level prior to stimulation. Spectral analysis indicated that cutaneous afferents also have a long-lasting memory effect on the tremor frequency, i.e. the tremor frequency post stimulation did not recover to the value prior to stimulation. Preliminary results implied that the reduction in tremor amplitude and EMGs could be due to the inhibitory effects of cutaneous afferents to PNs, supporting the hypothesis that the PN network is involved in transmission of cortical tremor commands to peripheral muscles.

An optical-electrical neural `Optrode' is developed for quantitative optical spectroscopic assessment of cortical tissue damage around a neural implant. In contrast to other Optrodes which illuminate tissue for neural activation, this work uses bi-directional waveguides to obtain spectroscopic information from the tissue. An optical assessment has the potential for providing a real-time histological assessment, by quantifying changes in absorption and scattering properties associated with oxygenation and tissue density around the neural probe, in contrast to impedance spectroscopy which provides limited insight. Optrode performance is characterized in optical tissue phantoms and a proof-of-concept chronic rat model is developed. Optrodes were chronically implanted in rat cerebral cortex. The pilot study demonstrates feasibility for chronic optical assessment. Future Optrodes may lead to high throughput and real-time assessments for studying the dynamic nature of the foreign body response in neural tissue.

The goal of fixation is to rapidly and uniformly preserve tissue in a life-like state. While placing tissue directly in fixative works well for small pieces of tissue, larger specimens like the intact brain pose a problem for immersion fixation because the fixative does not reach all regions of the tissue at the same rate (5,7). Often, changes in response to hypoxia begin before the tissue can be preserved (12). The advantage of directly perfusing fixative through the circulatory system is that the chemical can quickly reach every corner of the organism using the natural vascular network. In order to utilize the circulatory system most effectively, care must be taken to match physiological pressures (3). It is important to note that physiological pressures are dependent on the species used. Techniques for perfusion fixation vary depending on the tissue to be fixed and how the tissue will be processed following fixation. In this video, we describe a low-cost, rapid, controlled and uniform fixation procedure using 4% paraformaldehyde perfused via the vascular system: through the heart of the rat to obtain the best possible preservation of the brain for immunohistochemistry. The main advantage of this technique (vs. gravity-fed systems) is that the circulatory system is utilized most effectively.

Neural probe insertion methods have a direct impact on the longevity of the device in the brain. Initial tissue and vascular damage caused by the probe entering the brain triggers a chronic tissue response that is known to attenuate neural recordings and ultimately encapsulate the probes. Smaller devices have been found to evoke reduced inflammatory response. One way to record from undamaged neural networks may be to position the electrode sites away from the probe. To investigate this approach, we are developing probes with controllably movable electrode projections, which would move outside of the zone that is damaged by the insertion of the larger probe. The objective of this study was to test the capability of conjugated polymer bilayer actuators to actuate neural electrode projections from a probe shank into a transparent brain phantom. Parylene neural probe devices, having five electrode projections with actuating segments and with varying widths (50 - 250 μm) and lengths (200 - 1000 μm) were fabricated. The electroactive polymer polypyrrole (PPy) was used to bend or flatten the projections. The devices were inserted into the brain phantom using an electronic microdrive while simultaneously activating the actuators. Deflections were quantified based on video images. The electrode projections were successfully controlled to either remain flat or to actuate out-of-plane and into the brain phantom during insertion. The projection width had a significant effect on their ability to deflect within the phantom, with thinner probes deflecting but not the wider ones. Thus, small integrated conjugated polymer actuators may enable multiple neuro-experiments and applications not possible before.

Electrical impedance spectroscopy (EIS) and cyclic voltammetry (CV) measure properties of the electrode-tissue interface without additional invasive procedures, and can be used to monitor electrode performance over the long term. EIS measures electrical impedance at multiple frequencies, and increases in impedance indicate increased glial scar formation around the device, while cyclic voltammetry measures the charge carrying capacity of the electrode, and indicates how charge is transferred at different voltage levels. As implanted electrodes age, EIS and CV data change, and electrode sites that previously recorded spiking neurons often exhibit significantly lower efficacy for neural recording. The application of a brief voltage pulse to implanted electrode arrays, known as rejuvenation, can bring back spiking activity on otherwise silent electrode sites for a period of time. Rejuvenation alters EIS and CV, and can be monitored by these complementary methods. Typically, EIS is measured daily as an indication of the tissue response at the electrode site. If spikes are absent in a channel that previously had spikes, then CV is used to determine the charge carrying capacity of the electrode site, and rejuvenation can be applied to improve the interface efficacy. CV and EIS are then repeated to check the changes at the electrode-tissue interface, and neural recordings are collected. The overall goal of rejuvenation is to extend the functional lifetime of implanted arrays.

Advanced fabrication techniques have now made it possible to produce microelectrode arrays for recording the electrical activity of a large number of neurons in the intact brain for both clinical and basic science applications. However, the long-term recording performance desired for these applications is hindered by a number of factors that lead to device failure or a poor signal-to-noise ratio (SNR). The goal of this study was to identify factors that can affect recording quality using theoretical analysis of intracortical microelectrode recordings of single-unit activity. Extracellular microelectrode recordings were simulated with a detailed multi-compartment cable model of a pyramidal neuron coupled to a finite element volume conductor head model containing an implanted recording microelectrode. Recording noise sources were also incorporated into the overall modeling infrastructure. The analyses of this study would be very difficult to perform experimentally; however, our model-based approach enabled a systematic investigation of the effects of a large number of variables on recording quality. Our results demonstrate that recording amplitude and noise are relatively independent of microelectrode size, but instead are primarily affected by the selected recording bandwidth, impedance of the electrode-tissue interface, and the density and firing rates of neurons surrounding the recording electrode. This study provides the theoretical groundwork that allows for the design of the microelectrode and recording electronics such that the SNR is maximized. Such advances could help enable the long-term functionality required for chronic neural recording applications.

While the development of microelectrode arrays has enabled access to disparate regions of a cortex for neurorehabilitation, neuroprosthetic and basic neuroscience research, accurate interpretation of the signals and manipulation of the cortical neurons depend upon the anatomical placement of the electrode arrays in a layered cortex. Toward this end, this report compares two in vivo methods for identifying the placement of electrodes in a linear array spaced 100 µm apart based on in situ laminar analysis of (1) ketamine-xylazine-induced field potential oscillations in a rat motor cortex and (2) an intracortical electrical stimulation-induced movement threshold. The first method is based on finding the polarity reversal in laminar oscillations which is reported to appear at the transition between layers IV and V in laminar 'high voltage spindles' of the rat cortical column. Analysis of histological images in our dataset indicates that polarity reversal is detected 150.1 ± 104.2 µm below the start of layer V. The second method compares the intracortical microstimulation currents that elicit a physical movement for anodic versus cathodic stimulation. It is based on the hypothesis that neural elements perpendicular to the electrode surface are preferentially excited by anodic stimulation while cathodic stimulation excites those with a direction component parallel to its surface. With this method, we expect to see a change in the stimulation currents that elicits a movement at the beginning of layer V when comparing anodic versus cathodic stimulation as the upper cortical layers contain neuronal structures that are primarily parallel to the cortical surface and lower layers contain structures that are primarily perpendicular. Using this method, there was a 78.7 ± 68 µm offset in the estimate of the depth of the start of layer V. The polarity reversal method estimates the beginning of layer V within ±90 µm with 95% confidence and the intracortical stimulation method estimates it within ±69.3 µm. We propose that these methods can be used to estimate the in situ location of laminar electrodes implanted in the rat motor cortex.

Implantable neural microelectrodes that can record extracellular biopotentials from small, targeted groups of neurons are critical for neuroscience research and emerging clinical applications including brain-controlled prosthetic devices. The crucial material-dependent problem is developing microelectrodes that record neural activity from the same neurons for years with high fidelity and reliability. Here, we report the development of an integrated composite electrode consisting of a carbon-fibre core, a poly(p-xylylene)-based thin-film coating that acts as a dielectric barrier and that is functionalized to control intrinsic biological processes, and a poly(thiophene)-based recording pad. The resulting implants are an order of magnitude smaller than traditional recording electrodes, and more mechanically compliant with brain tissue. They were found to elicit much reduced chronic reactive tissue responses and enabled single-neuron recording in acute and early chronic experiments in rats. This technology, taking advantage of new composites, makes possible highly selective and stealthy neural interface devices towards realizing long-lasting implants.

A new parylene-based microfabrication process is presented for neural recording and drug delivery applications. We introduce a large design space for electrode placement and structural flexibility with a six mask process. By using chemical mechanical polishing, electrode sites may be created top-side, back-side, or on the edge of the device having three exposed sides. Added surface area was achieved on the exposed edge through electroplating. Poly(3,4-ethylenedioxythiophene) (PEDOT) modified edge electrodes having an 85-μm(2) footprint resulted in an impedance of 200 kΩ at 1 kHz. Edge electrodes were able to successfully record single unit activity in acute animal studies. A finite element model of planar and edge electrodes relative to neuron position reveals that edge electrodes should be beneficial for increasing the volume of tissue being sampled in recording applications.

The collagenous dura mater requires a secure closure following implantation of neural prosthetic devices to avoid complications due to cerebrospinal fluid leakage and infections. Alginate was previously suggested for use as a dural sealant. The liquid application and controllable gelling conditions enable alginate to conform to the unique geometries of a neural prosthetic device and the surrounding dura mater to create a barrier with the external environment. In this study, we evaluated the use of alginate as a method to securely reclose a dural defect and seal around an untethered microscale neural probe in the rabbit model. After 3 days and 3 weeks, the sealing strength of alginate remained eight times greater than normal rabbit intracranial pressure and similar in both the presence and absence of a penetrating neural probe. For time points up to 3 months, there was no significant difference in dura mater fibrosis or thickness between alginate and controls. Application of alginate to a dural defect results in a watertight seal that remains intact while the dura mater reforms. These findings indicate that alginate is an effective tool for sealing around microscale neural probes and suggests broader application as a sealant for larger neural prosthetic devices.

Most implantable chronic neural probes have fixed electrode sites on the shank of the probe. Neural probe shapes and insertion methods have been shown to have considerable effects on the resulting chronic reactive tissue response that encapsulates probes. We are developing probes with controllable articulated electrode projections, which are expected to provoke less reactive tissue response due to the projections being minimally sized, as well as to permit a degree of independence from the probe shank allowing the recording sites to "float" within the brain. The objective of this study was to predict and analyze the force-generating capability of conducting polymer bilayer actuators under physiological settings. Custom parylene beams 21 μm thick, 1 cm long, and of varying widths (200 - 1000 μm) were coated with Cr/Au. Electroplated weights were fabricated at the ends of the beams to apply known forces. Polypyrrole was potentiostatically polymerized to varying thicknesses onto the Au at 0.5 V in a solution of 0.1 M pyrrole and 0.1 M dodecylbenzenesulfonate (DBS). Using cyclic voltammetry, the bilayer beams were cycled in artificial cerebrospinal fluid (aCSF) at 37 °C, as well as in aqueous NaDBS as a control. Digital images and video were analyzed to quantify the deflections. The images and the cyclic voltammograms showed that divalent cations in the aCSF interfered with polymer reduction. By integrating polypyrrole-based conducting polymer actuators, we present a type novel neural probe. We demonstrate that actuating PPy(DBS) under physiological settings is possible, and that the technique of microfabricating weights onto the actuators is a useful tool for studying actuation forces.

The collagenous dura mater isolates the brain from the external environment and requires a secure closure following invasive neurosurgery. This is typically accomplished by approximation of the dura mater via sutures and adhesives. In selected cases, however, large portions of dura mater require excision, necessitating a tissue replacement patch. The mild reaction conditions and long-term biocompatibility of alginate evince strong candidacy for these applications. This study investigates the potential of diffusion and internally gelled alginates for these applications. Specifically, we quantified the viscosity, gel rate, syneresis level, compressive strength, compressive modulus, complex modulus and loss angle in the context of dura mater repair. The ideal sealant would have a rapid cross-link speed, while the ideal dura mater replacement would have a low level of syneresis. Both applications require a compressive modulus of 20–100 kPa and a complex modulus of 1–24 kPa. The data collected in this study suggests that the use of 1.95 wt% 43 mPa s alginate with 200 mM CaCl2 is sufficient for approximating the dural membrane for closure alone or in conjunction with suture. Alternatively, the use of 1.95 wt% 43 mPa s alginate with 100 mM CaCO3 is sufficient for tissue replacement in large dural defects.

Closed-loop neural interface technology that combines neural ensemble decoding with simultaneous electrical microstimulation feedback is hypothesized to improve deep brain stimulation techniques, neuromotor prosthetic applications, and epilepsy treatment. Here we describe our iterative results in a rat model of a sensory and motor neurophysiological feedback control system. Three rats were chronically implanted with microelectrode arrays in both the motor and visual cortices. The rats were subsequently trained over a period of weeks to modulate their motor cortex ensemble unit activity upon delivery of intra-cortical microstimulation (ICMS) of the visual cortex in order to receive a food reward. Rats were given continuous feedback via visual cortex ICMS during the response periods that was representative of the motor cortex ensemble dynamics. Analysis revealed that the feedback provided the animals with indicators of the behavioral trials. At the hardware level, this preparation provides a tractable test model for improving the technology of closed-loop neural devices.

The purpose of this study is to optimize poly(3,4,- ethylenedioxythiophene) (PEDOT) polymerization into decellular nerve scaffolding for interfacing to peripheral nerves. Our ultimate aim is to permanently implant highly conductive peripheral nerve interfaces between amputee, stump, nerve fascicles and prosthetic electronics. Decellular nerve (DN) scaffolds are an FDA approved biomaterial (Axogen TM ) with the flexible tensile properties needed for successful permanent coaptation to peripheral nerves. Biocompatible, electroconductive, PEDOT facilitates electrical conduction through PEDOT coated acellular muscle. New electrochemical methods were used to polymerize various PEDOT concentrations into DN scaffolds without the need for a final dehydration step. DN scaffolds were then tested for electrical impedance and charge density. PEDOT coated DN scaffold materials were also implanted as 15-20mm peripheral nerve grafts. Measurement of in-situ nerve conduction immediately followed grafting. DN showed significant improvements in impedance for dehydrated and hydrated, DN, polymerized with moderate and low PEDOT concentrations when they were compared with DN alone (a≤ 0.05). These measurements were equivalent to those for DN with maximal PEDOT concentrations. In-situ, nerve conduction measurements demonstrated that DN alone is a poor electro-conductor while the addition of PEDOT allows DN scaffold grafts to compare favorably with the “gold standard”, autograft (Table 1). Surgical handling characteristics for conductive hydrated PEDOT DN scaffolds were rated 3 (pliable) while the dehydrated models were rated 1 (very stiff) when compared with autograft ratings of 4 (normal). Low concentrations of PEDOT on DN scaffolds provided significant increases in electro active properties which were comparable to the densest PEDOT coatings. DN pliability was closely maintained by continued hydration during PEDOT electrochemical polymerization without compromising electroconductivity.