Measuring the Electrical Stapedius Reflex with Stapedius Muscle Electromyogram Recordings

Annals of Biomedical Engineering. Feb, 2002  |  Pubmed ID: 11962769

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.

Flow Properties of Liquid Calcium Alginate Polymer Injected Through Medical Microcatheters for Endovascular Embolization

Journal of Biomedical Materials Research. Sep, 2002  |  Pubmed ID: 12115443

The flow properties of liquid calcium alginate injections were investigated for application in endovascular embolization. Alginate shear properties were assessed with a rheometer and a controlled injection system. The experimental results were used to model the flow properties and predict alginate's flow characteristics within various medical microcatheter delivery systems. The results suggest that alginates undergo shear-thinning effects with increasing shear. A flow comparison of 2.0 wt % alginate and a Newtonian fluid (82 cP) injected from the same microcatheter had similar flow rates at low injection pressure (100 kPa). However, at high injection pressure (2100 kPa), the alginate was injectable at a flow rate 100% higher than was the Newtonian fluid. Further analysis of injections through microcatheters resulted in a flow model for predicting viscosity changes, flow rates, and injection pressures of liquid alginate at medium-to-high shear rates. The predicted injection pressures and flow rates had an average variance of less than 15% from that of the experimental flow data. This study indicates that calcium alginate has the requisite flow properties for successful delivery to vascular lesions via endovascular injection. Possible uses of alginates include treating arteriovenous malformations (AVMs), aneurysms, blood flow to tumors, and vascular hemorrhages.

In Vivo Assessment of Calcium Alginate Gel for Endovascular Embolization of a Cerebral Arteriovenous Malformation Model Using the Swine Rete Mirabile

Neurosurgery. Aug, 2002  |  Pubmed ID: 12182784

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.

Single Electrode Micro-stimulation of Rat Auditory Cortex: an Evaluation of Behavioral Performance

Hearing Research. May, 2003  |  Pubmed ID: 12742239

A combination of electrophysiological mapping, behavioral analysis and cortical micro-stimulation was used to explore the interrelation between the auditory cortex and behavior in the adult rat. Auditory discriminations were evaluated in eight rats trained to discriminate the presence or absence of a 75 dB pure tone stimulus. A probe trial technique was used to obtain intensity generalization gradients that described response probabilities to mid-level tones between 0 and 75 dB. The same rats were then chronically implanted in the auditory cortex with a 16 or 32 channel tungsten microwire electrode array. Implanted animals were then trained to discriminate the presence of single electrode micro-stimulation of magnitude 90 microA (22.5 nC/phase). Intensity generalization gradients were created to obtain the response probabilities to mid-level current magnitudes ranging from 0 to 90 microA on 36 different electrodes in six of the eight rats. The 50% point (the current level resulting in 50% detections) varied from 16.7 to 69.2 microA, with an overall mean of 42.4 (+/-8.1) microA across all single electrodes. Cortical micro-stimulation induced sensory-evoked behavior with similar characteristics as normal auditory stimuli. The results highlight the importance of the auditory cortex in a discrimination task and suggest that micro-stimulation of the auditory cortex might be an effective means for a graded information transfer of auditory information directly to the brain as part of a cortical auditory prosthesis.

Silicon-substrate Intracortical Microelectrode Arrays for Long-term Recording of Neuronal Spike Activity in Cerebral Cortex

IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. Jun, 2003  |  Pubmed ID: 12899260

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.

Characterization of Implantable Microfabricated Fluid Delivery Devices

IEEE Transactions on Bio-medical Engineering. Jan, 2004  |  Pubmed ID: 14723503

The formal characterization of the performance of microfluidic delivery devices is crucial for reliable in vivo application. A comprehensive laboratory technique was developed and used to optimize, calibrate and validate microfabricated fluid delivery devices. In vivo experiments were carried out to verify the accuracy and reliability of the pressure driven devices. Acute guinea pig experiments were conducted to measure the response to alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid, an excitatory neurotransmitter, at multiple locations in the inferior colliculus. A nondimensional parameter, Q, was successfully used to classify devices in terms of geometry alone (i.e., independent of fluid properties). Functional devices exhibited long-term linearity and reliability in delivering single phase, Newtonian fluids, in discrete volumes with a resolution of 500 picoliters at less than 0.45 lbf/in2 (30 mbar) pressure drop. Results for non-Newtonian fluids are not presented here. The acute results showed a proportional increase in the firing rate for delivered volumes of 2 nL up to 10 nL (at rates of between 0.1 and 1 nL/s). Flow characteristics are maintained during acute experiments and post-implant. A control experiment conducted with Ringer solution produced negligible effects, suggesting the results to be truly pharmacological. The experimental techniques employed have proven to be reliable and will be used for future calibration and testing of next generation chronic microfluidic delivery devices.

Chronic Neural Recording Using Silicon-substrate Microelectrode Arrays Implanted in Cerebral Cortex

IEEE Transactions on Bio-medical Engineering. Jun, 2004  |  Pubmed ID: 15188856

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.

Calcium Alginate Gel As a Biocompatible Material for Endovascular Arteriovenous Malformation Embolization: Six-month Results in an Animal Model

Neurosurgery. Apr, 2005  |  Pubmed ID: 15792518

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.

Enhanced Contrast Sensitivity in Auditory Cortex As Cats Learn to Discriminate Sound Frequencies

Brain Research. Cognitive Brain Research. May, 2005  |  Pubmed ID: 15820626

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.

Cortical Microstimulation in Auditory Cortex of Rat Elicits Best-frequency Dependent Behaviors

Journal of Neural Engineering. Jun, 2005  |  Pubmed ID: 15928411

Electrical activation of the auditory cortex has been shown to elicit an auditory sensation; however, the perceptual effects of auditory cortical microstimulation delivered through penetrating microelectrodes have not been clearly elucidated. This study examines the relationship between electrical microstimulus location within the adult rat auditory cortex and the subsequent behavior induced. Four rats were trained on an auditory frequency discrimination task and their lever-pressing behavior in response to stimuli of intermediate auditory frequencies was quantified. Each trained rat was then implanted with a microwire array in the auditory cortex of the left hemisphere. Best frequencies (BFs) of each electrode in the array were determined by both local field potential and multi-unit spike-rate activity evoked by pure tone stimuli. A cross-dimensional psychophysical generalization paradigm was used to evaluate cortical microstimulation-induced behavior. Using the BFs of each electrode, the microstimulation-induced behavior was evaluated relative to the auditory-induced behavior. Microstimulation resulted in behavior that was dependent on the BFs of the electrodes used for stimulation. These results are consistent with recent reports indicating that electrophysiological recordings of neural responses to sensory stimuli may provide insight into the sensation generated by electrical stimulation of the same sensory neural tissue.

Naive Coadaptive Cortical Control

Journal of Neural Engineering. Jun, 2005  |  Pubmed ID: 15928412

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 (P < 0.05, 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 (P < 0.01, 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 (P < 0.05, Z-test), while one subject demonstrated control above chance (P < 0.05, 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.

Repeated Voltage Biasing Improves Unit Recordings by Reducing Resistive Tissue Impedances

IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. Jun, 2005  |  Pubmed ID: 16003894

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 (Ren) from the model. Implants whose SNR effects lasted more than a day showed stabilized reductions in the extracellular tissue resistance (Rex) and cellular membrane area (Am). 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.

Microstimulation in Auditory Cortex Provides a Substrate for Detailed Behaviors

Hearing Research. Dec, 2005  |  Pubmed ID: 16209915

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.

Multi-site Incorporation of Bioactive Matrices into MEMS-based Neural Probes

Journal of Neural Engineering. Dec, 2005  |  Pubmed ID: 16317225

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.

A Finite-element Model of the Mechanical Effects of Implantable Microelectrodes in the Cerebral Cortex

Journal of Neural Engineering. Dec, 2005  |  Pubmed ID: 16317234

The viability of chronic neural microelectrodes for electrophysiological recording and stimulation depends on several factors, including the encapsulation of the implant by a reactive tissue response. We postulate that mechanical strains induced around the implant site may be one of the leading factors responsible for the sustained tissue response in chronic implants. The objectives of this study were to develop a finite-element model of the probe-brain tissue interface and analyze the effects of tethering forces, probe-tissue adhesion and stiffness of the probe substrate on the interfacial strains induced around the implant site. A 3D finite-element model of the probe-brain tissue microenvironment was developed and used to simulate interfacial strains created by 'micromotion' of chronically implanted microelectrodes. Three candidate substrates were considered: (a) silicon, (b) polyimide and (c) a hypothetical 'soft' material. Simulated tethering forces resulted in elevated strains both at the tip and at the sharp edges of the probe track in the tissue. The strain fields induced by a simulated silicon probe were similar to those induced by a simulated polyimide probe, albeit at higher absolute values for radial tethering forces. Simulations of poor probe-tissue adhesion resulted in elevated strains at the tip and delamination of the tissue from the probe. A tangential tethering force results in 94% reduction in the strain value at the tip of the polyimide probe track in the tissue, whereas the simulated 'soft' probe induced two orders of magnitude smaller values of strain compared to a simulated silicon probe. The model results indicate that softer substrates reduce the strain at the probe-tissue interface and thus may also reduce tissue response in chronic implants.

Voltage Pulses Change Neural Interface Properties and Improve Unit Recordings with Chronically Implanted Microelectrodes

IEEE Transactions on Bio-medical Engineering. Feb, 2006  |  Pubmed ID: 16485763

Current neuroprosthetic systems based on electro-physiological 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% +/- 2%), with a maximal increase of 195% from 3.74 to 11.02. Rejuvenation also reduced the electrode site impedances at 1 kHz (67% +/- 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% +/- 7%). These findings suggest that rejuvenation may be an intervention strategy to prolong the functional lifetime of chronically implanted microelectrodes.

Chronic Neural Recordings Using Silicon Microelectrode Arrays Electrochemically Deposited with a Poly(3,4-ethylenedioxythiophene) (PEDOT) Film

Journal of Neural Engineering. Mar, 2006  |  Pubmed ID: 16510943

Conductive polymer coatings can be used to modify traditional electrode recording sites with the intent of improving the long-term performance of cortical microelectrodes. Conductive polymers can drastically decrease recording site impedance, which in turn is hypothesized to reduce thermal noise and signal loss through shunt pathways. Moreover, conductive polymers can be seeded with agents aimed at promoting neural growth toward the recording sites or minimizing the inherent immune response. The end goal of these efforts is to generate an ideal long-term interface between the recording electrode and surrounding tissue. The goal of this study was to refine a method to electrochemically deposit surfactant-templated ordered poly(3,4-ethylenedioxythiophene) (PEDOT) films on the recording sites of standard 'Michigan' probes and to evaluate the efficacy of these modified sites in recording chronic neural activity. PEDOT-coated site performance was compared to control sites over a six-week evaluation period in terms of impedance spectroscopy, signal-to-noise ratio, number of viable unit potentials recorded and local field potential recordings. PEDOT sites were found to outperform control sites with respect to signal-to-noise ratio and number of viable unit potentials. The benefit of reduced initial impedance, however, was mitigated by the impedance contribution of typical silicon electrode encapsulation. Coating sites with PEDOT also reduced the amount of low-frequency drift evident in local field potential recordings. These findings indicate that electrode sites electrochemically deposited with PEDOT films are suitable for recording neural activity in vivo for extended periods. This study also provided a unique opportunity to monitor how neural recording characteristics develop over the six weeks following implantation.

Laminar Analysis of Movement Direction Information in Local Field Potentials of the Rat Motor Cortex

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17946968

Local field potentials (LFPs) have been proposed for use in controlling neural prosthetic devices because they can provide reliable motor and sensory-related information, and can easily be recorded over long periods of time. While studies have shown that directional information about motor movements can be inferred from LFPs, it is not known at what depth these signals should be recorded from in order to maximize the amount of movement information. Towards this end, we used a directional motor task in Long Evans rats, while sampling LFPs with an electrode consisting of 16 vertical recording sites that were evenly-spaced 100 microm apart. This allowed for simultaneous recording of all layers of the motor cortex. The frequency components of LFPs were then analyzed using k-means clustering to determine directional information as a function of depth. Here we report our initial findings that superficial layers (II/III) of motor cortex may provide more information about movement directions then deeper layers (V).

Neural Interface Dynamics Following Insertion of Hydrous Iridium Oxide Microelectrode Arrays

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17947012

Studies examining traumatic brain injury have suggested a 'window of opportunity' exists for therapeutic agents to mitigate edema and cellular toxicity effectively. However, successful therapy also relies on identifying the extent of blood-brain barrier disruption, which is associated with excessive extra-cellular concentrations of ions, excitatory amino acids, and serum proteins. The following study investigates the use of pH-selective hydrous iridium oxide microelectrodes to assess trauma following insertion of a neural probe. Electrochemical activation of iridium microelectrode arrays was performed in either acidic (0.5 M H2SO4) or weak basic (0.3 M Na2HPO4, pH=8.56) solutions. Both oxides demonstrated super-Nernstian pH sensitivity (-88.5 mV/pH and -77.1 mV/pH, respectively) with little interference by other cations. Data suggest that acid-grown oxide provides better potential stability than base-grown oxide (sigma=2.8 versus 4.9 mV over 5 hours). Implantation of these electrodes into motor cortex and dorsal striatum revealed significant acidosis during and following insertion. Variability in the spatiotemporal pH profile included micro-scale inhomogeneities along the probe shank and significant differences in the averaged pH response between successive insertions using the same depth and speed. This diagnostic technology has important implications for intervention therapies in order to more effectively treat acute surgical brain trauma.

Optimization of Microelectrode Design for Cortical Recording Based on Thermal Noise Considerations

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17947023

Intracortical microelectrode recordings of neural activity show great promise as control signals for neuroprosthetic applications. However, faithful, consistent recording of single unit spiking activity with chronically implanted silicon-substrate microelectrode arrays has proven difficult. Many approaches seek to enhance the long-term performance of microelectrode arrays by, for example, increasing electrode biocompatibility, decreasing electrode impedance, or improving electrode interface properties through application of small voltage pulses. The purpose of this study was to use computational models to optimize the design of microelectrodes. We coupled detailed models of the neural source signal, silicon-substrate microelectrodes, and thermal noise to define the electrode contact size that maximized the signal-to-noise ratio (SNR). Model analysis combined a multi-compartment cable model of a layer V cortical pyramidal neuron with a 3D finite element model of the head and microelectrode to define the amplitude and time course of the recorded signal. A spatially-lumped impedance model was parameterized with in vitro and in vivo spectroscopy data and used to define thermal noise as a function of electrode contact size. Our results suggest that intracortical microelectrodes with a contact size of ~380 microm2 will provide an increased SNR in vivo and improve the long-term recording capabilities of silicon-substrate microelectrode arrays.

The Role of Flexible Polymer Interconnects in Chronic Tissue Response Induced by Intracortical Microelectrodes--a Modeling and an in Vivo Study

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17947041

Chronic tissue response induced by tethering is one of the major causes for implant failure in intracortical microelectrodes. In this study, we had explored the hypothesis that flexible interconnects could provide strain relief against forces of "micromotion" and hence could result in maintaining a healthy tissue surrounding the implant. Finite element modeling results indicated that flexible interconnects, namely polyimide (E=2 GPa) and polydimethylsiloxane (PDMS, E=6 MPa), reduced the interfacial strain by 66% and two orders of magnitude, respectively. Quantitative immunohistochemistry results indicated that significant neuronal loss occurred up to 60 mum from the implant interface. This was strongly correlated to both glial fibrillary acidic protein (GFAP) expression and simulated strain as a function of distance away from the implant.

Fabrication of Polymer Neural Probes with Sub-cellular Features for Reduced Tissue Encapsulation

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17947102

Intracortical microelectrodes currently have great potential as a neural prosthesis in patients with neurodegenerative disease or spinal cord injury. In an effort to improve the consistency of neural probe performance, many modifications to probe design are focused on reducing the tissue encapsulation. Since researchers have shown that small polymer fibers (less than 7-microm diameter) induce a small to non-existent encapsulation layer in the rat subcutis, we have proposed a neural probe design with similarly small diameter structures. This paper discusses the fabrication and design parameters of a microscale neural probe with a sub-cellular lattice structure. We developed a microfabrication process using SU-8 and parylene-C to create the relatively thick probe shank and thin lateral arms. The stiff penetrating shank (70-microm by 42-microm) had an SU-8 core that allowed control over stiffness and simplified the process. Parylene-only structures lateral to the shank could be defined with a 4-microm feature-size to meet our sub-cellular criterion. We fabricated four varying geometries for implantation into the neocortex of seven Sprague-Dawley rats. Our in vivo testing verifies that despite the flexible substrate and small dimensions (4-microm x 5-microm), these devices are mechanically robust and practical as neural probes. These devices provide an important tool for neural engineers to investigate the tissue response around sub-cellular structures and potentially improve device efficacy.

Suitability of the Cingulate Cortex for Neural Control

IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. Dec, 2006  |  Pubmed ID: 17190032

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.

Fast Wave Propagation in Auditory Cortex of an Awake Cat Using a Chronic Microelectrode Array

Journal of Neural Engineering. Jun, 2007  |  Pubmed ID: 17409481

We investigated fast wave propagation in auditory cortex of an alert cat using a chronically implanted microelectrode array. A custom, real-time imaging template exhibited wave dynamics within the 33-microwire array (3 mm(2)) during ten recording sessions spanning 1 month post implant. Images were based on the spatial arrangement of peri-stimulus time histograms at each recording site in response to auditory stimuli consisting of tone pips between 1 and 10 kHz at 75 dB SPL. Functional images portray stimulus-locked spiking activity and exhibit waves of excitation and inhibition that evolve during the onset, sustained and offset period of the tones. In response to 5 kHz, for example, peak excitation occurred at 27 ms after onset and again at 15 ms following tone offset. Variability of the position of the centroid of excitation during ten recording sessions reached a minimum at 31 ms post onset (sigma = 125 microm) and 18 ms post offset (sigma = 145 microm), suggesting a fine place/time representation of the stimulus in the cortex. The dynamics of these fast waves also depended on stimulus frequency, likely reflecting the tonotopicity in auditory cortex projected from the cochlea. Peak wave velocities of 0.2 m s(-1) were also consistent with those purported across horizontal layers of cat visual cortex. The fine resolution offered by microimaging may be critical for delivering optimal coding strategies used with an auditory prosthesis. Based on the initial results, future studies seek to determine the relevance of these waves to sensory perception and behavior.

Neural Probe Design for Reduced Tissue Encapsulation in CNS

Biomaterials. Sep, 2007  |  Pubmed ID: 17517431

This study investigated relationships between a microscale neural probe's size and shape and its chronic reactive tissue response. Parylene-based probes were microfabricated with a thick shank (48 microm by 68 microm) and an integrated thin lateral platform (5 microm by 100 microm, either solid or one of three lattice sizes). Devices were implanted in rat cerebral cortex for 4 weeks before immunostaining for neurons, astrocytes, microglia, fibronectin, laminin, and neurofilament. While nonneuronal density (NND) generally increased and neuronal density decreased within 75 microm of a probe interface compared to unimplanted control regions, there were significant differential tissue responses within 25 microm of the platform's lateral edge compared to the shank. The NND in this region of the lateral edge was less than one-third of the corresponding region of the shank (129% and 425% increase, respectively). Moreover, neuronal density around the platform lateral edge was about one-third higher than at the shank (0.70 and 0.52 relative to control, respectively). Also, microglia reactivity and extracellular protein deposition was reduced at the lateral edge. There were no significant differences among platform designs. These results suggest that neural probe geometry is an important parameter for reducing chronic tissue encapsulation.

Preliminary Investigation of Calcium Alginate Gel As a Biocompatible Material for Endovascular Aneurysm Embolization in Vivo

Neurosurgery. Jun, 2007  |  Pubmed ID: 17538387

We sought to expand our assessment of calcium alginate as an embolic agent in an aneurysm model in swine that survived from 30 to 90 days. The objective of this study was to assess the biocompatibility and stability of calcium alginate in aneurysms in vivo.

In Vivo Stability and Biocompatibility of Implanted Calcium Alginate Disks

Journal of Biomedical Materials Research. Part A. Dec, 2007  |  Pubmed ID: 17595019

Alginate is a commonly used biomedical hydrogel whose in vivo degradation behavior is only beginning to be understood. The use of alginate in the central nervous system is gaining popularity as an electrode coating, cell encapsulation matrix, and for duraplasty. However, it is necessary to understand how the hydrogel will behave in vivo to aid in the development of alginate for use as a neural interface material. The goal of the current study was to compare the rheological behavior of explanted alginate disks and the inflammatory response to subcutaneously implanted alginate hydrogels over a 3-month period. Specifically, the effects due to (1) in situ gelling, (2) diffusion gelling, and (3) use of a poly-l-lysine (PLL) coating were investigated. While all samples' complex moduli decreased 80% in the first day, in situ gelled alginate was more stable for the first week of implantation. The PLL coating offered some stability increases for diffusion gelled alginate, but the stability in both conditions remained significantly lower than that in in situ gelled alginate. There were no differences in biocompatibility that clearly suggested one gelation method over another. These results indicate that in situ gelation is the preferred method in neural interface applications where stability is the primary concern.

Complex Impedance Spectroscopy for Monitoring Tissue Responses to Inserted Neural Implants

Journal of Neural Engineering. Dec, 2007  |  Pubmed ID: 18057508

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.

Spatiotemporal PH Dynamics Following Insertion of Neural Microelectrode Arrays

Journal of Neuroscience Methods. Mar, 2007  |  Pubmed ID: 17084461

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<0.05). Spatiotemporal analysis of the recordings also revealed micro-scale variability in the pH(e) response along the array, even when using the same insertion technique. Implants with more intense acidosis were often associated histologically with blood along the probe tract. The potentiometric microsensor array has implications not only as a useful tool to measure extracellular pH, but also as a feedback tool for delivery of pharmacological agents to treat surgical brain trauma.

Implantable Microelectrode Arrays for Simultaneous Electrophysiological and Neurochemical Recordings

Journal of Neuroscience Methods. Sep, 2008  |  Pubmed ID: 18692090

Implantable microfabricated microelectrode arrays represent a versatile and powerful tool to record electrophysiological activity across multiple spatial locations in the brain. Spikes and field potentials, however, correspond to only a fraction of the physiological information available at the neural interface. In urethane-anesthetized rats, microfabricated microelectrode arrays were implanted acutely for simultaneous recording of striatal local field potentials, spikes, and electrically evoked dopamine overflow on the same spatiotemporal scale. During these multi-modal recordings we observed (1) that the amperometric method used to detect dopamine did not significantly influence electrophysiological activity, (2) that electrical stimulation in the medial forebrain bundle (MFB) region resulted in electrochemically transduced dopamine transients in the striatum that were spatially heterogeneous within at least 200 microm, and (3) following MFB stimulation, dopamine levels and electrophysiological activity within the striatum exhibited similar temporal profiles. These neural probes are capable of incorporating customized microelectrode geometries and configurations, which may be useful for examining specific spatiotemporal relationships between electrical and chemical signaling in the brain.

Advanced Neurotechnologies for Chronic Neural Interfaces: New Horizons and Clinical Opportunities

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Nov, 2008  |  Pubmed ID: 19005048

Cytotoxic Analysis of the Conducting Polymer PEDOT Using Myocytes

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2008  |  Pubmed ID: 19163041

Biosensors interact with biological systems at the surface of the sensor. Coating these sensors with electrically active polymers has been suggested to improve this interface. The electrically conducting polymer poly (3, 4 ethylenedioxythiophene) (PEDOT) enhances electrical recordings by improving conductivity while maintaining chemical stability. It also offers great flexibility in studying cell substrate interactions because of the variety of counter-ions that can be incorporated into the PEDOT matrix. To provide any true benefit in cell culture or in vivo experiments, the cytotoxicity of PEDOT must first be determined. This study evaluated the cytotoxicity of PEDOT doped with either polystyrene sulfonate (PSS) or phosphate buffered saline (PBS) ions and tested the efficacy of using the conductive PEDOT substrates for myoblast proliferation and differentiation. Results show that PEDOT/PBS and PEDOT/PSS are not cytotoxic to cells and successfully support cellular proliferation and differentiation. These results establish PEDOT as a material for cell-substrate interface studies. With biosensors being modified using the new polymer coating PEDOT, this cytotoxicity study provides evidence that PEDOT coatings will not induce a cytotoxic response when implanted in vivo.

Lower Layers in the Motor Cortex Are More Effective Targets for Penetrating Microelectrodes in Cortical Prostheses

Journal of Neural Engineering. Apr, 2009  |  Pubmed ID: 19255460

Improving cortical prostheses requires the development of recording neural interfaces that are efficient in terms of providing maximal control information with minimal interface complexity. While the typical approaches have targeted neurons in the motor cortex with multiple penetrating shanks, an alternative approach is to determine an efficient distribution of electrode sites within the layers of the cortex with fewer penetrating shanks. The objective of this study was to compare unit activity in the upper and lower layers of the cortex with respect to movement and direction in order to inform the design of penetrating microelectrodes. Four rats were implanted bilaterally with multi-site single-shank silicon microelectrode arrays in the neck/shoulder region of the motor cortex. We simultaneously recorded unit activity across all layers of the motor cortex while the animal was engaged in a movement direction task. Localization of the electrode array within the different layers of the cortex was determined by histology. We denoted units from layers 2 and 3 and units as upper layer units, and units from layers 5 and 6 as lower layer units. Analysis of unit spiking activity demonstrated that both the upper and lower layers encode movement and direction information. Unit responses in either cortical layer of the cortex were not preferentially associated with contralateral or ipsilateral movement. Aggregate analysis (633 neurons) and best session analysis (75 neurons) indicated that units in the lower layers (layers 5, 6) are more likely to encode direction information when compared to units in the upper layers (layers 2, 3) (p< 0.05). These results suggest that electrode sites clustered in the lower layers provide access to more salient control information for cortical neuroprostheses.

Alginate Composition Effects on a Neural Stem Cell-seeded Scaffold

Tissue Engineering. Part C, Methods. Dec, 2009  |  Pubmed ID: 19368511

The purpose of this study was to evaluate the effects of alginate composition on the neurotrophic factor release, viability, and proliferation of encapsulated neural stem cells (NSCs), as well as on the mechanical stability of the scaffold itself. Four compositions were tested: a high guluronic acid (68%) and a high mannuronic acid (54%) content alginate, with or without a poly-L-lysine (PLL) coating layer. Enzyme-linked immunosorbent assay was used to quantify the release of brain-derived neurotrophic factor, glial-derived neurotrophic factor, and nerve growth factor from the encapsulated cells. All three factors were detected from encapsulated cells only when a high L-guluronic acid alginate without PLL was used. Additionally, capsules with this composition remained intact more frequently when exposed to solutions of low osmolarity, potentially indicating superior mechanical stability. Alginate beads with a PLL-coated, high D-mannuronic acid composition were the most prone to breakage in the osmotic pressure test, and were too fragile for histology and proliferation assays after 1 week in vitro. NSCs survived and proliferated in the three remaining alginate compositions similarly over the 21-day study course irrespective of scaffold condition. NSC-seeded alginate beads with a high L-guluronic acid, non-PLL-coated composition may be useful in the repair of injured nervous tissue, where the mechanism is the secretion of neuroprotective factors. We verify the neuroprotective effects of medium conditioned by NSC-seeded alginate beads on the serum withdrawal-mediated death of PC-12 cells here.

Flavopiridol Reduces the Impedance of Neural Prostheses in Vivo Without Affecting Recording Quality

Journal of Neuroscience Methods. Oct, 2009  |  Pubmed ID: 19560490

We hypothesized that re-entry into the cell cycle may be associated with reactive gliosis surrounding neural prostheses, and that administration of a cell cycle inhibitor (flavopiridol) at the time of surgery would reduce this effect. We investigated the effects of flavopiridol on recording quality and impedance over a 28-day time period and conducted histology at 3 and 28 days post-implantation. Flavopiridol reduced the expression of a cell cycle protein (cyclin D1) in microglia surrounding probes at the 3-day time point. Impedance at 1 kHz was decreased by drug administration across the study period compared to vehicle controls. Correlations between recording (SNR, units) and impedance metrics revealed a small, but statistically significant, inverse relationship between these variables. However, the relationship between impedance and recording quality was not sufficiently strong for flavopiridol to result in an improvement in SNR or the number of units detected. Our data indicate that flavopiridol is an effective, easily administered treatment for reducing impedance in vivo, potentially through inhibiting microglial encapsulation of implanted devices. This strategy may be useful in stimulation applications, where reduced impedance is desirable for achieving activation thresholds and prolonging the lifetime of the implanted power supply. While improvements in recording quality were not observed, a combination of flavopiridol with a second strategy which enhances neuronal signal detection may enhance these results in future studies.

In Vivo Performance of a Microelectrode Neural Probe with Integrated Drug Delivery

Neurosurgical Focus. Jul, 2009  |  Pubmed ID: 19569896

The availability of sophisticated neural probes is a key prerequisite in the development of future brain-machine interfaces (BMIs). In this study, the authors developed and validated a neural probe design capable of simultaneous drug delivery and electrophysiology recordings in vivo. Focal drug delivery promises to extend dramatically the recording lives of neural probes, a limiting factor to clinical adoption of BMI technology.

Using a Common Average Reference to Improve Cortical Neuron Recordings from Microelectrode Arrays

Journal of Neurophysiology. Mar, 2009  |  Pubmed ID: 19109453

In this study, we propose and evaluate a technique known as common average referencing (CAR) to generate a more ideal reference electrode for microelectrode recordings. CAR is a computationally simple technique, and therefore amenable to both on-chip and real-time applications. CAR is commonly used in EEG, where it is necessary to identify small signal sources in very noisy recordings. To study the efficacy of common average referencing, we compared CAR to both referencing with a stainless steel bone-screw and a single microelectrode site. Data consisted of in vivo chronic recordings in anesthetized Sprague-Dawley rats drawn from prior studies, as well as previously unpublished data. By combining the data from multiple studies, we generated and analyzed one of the more comprehensive chronic neural recording datasets to date. Reference types were compared in terms of noise level, signal-to-noise ratio, and number of neurons recorded across days. Common average referencing was found to drastically outperform standard types of electrical referencing, reducing noise by >30%. As a result of the reduced noise floor, arrays referenced to a CAR yielded almost 60% more discernible neural units than traditional methods of electrical referencing. CAR should impart similar benefits to other microelectrode recording technologies-for example, chemical sensing-where similar differential recording concepts apply. In addition, we provide a mathematical justification for CAR using Gauss-Markov theorem and therefore help place the application of CAR into a theoretical context.

Insertion Shuttle with Carboxyl Terminated Self-assembled Monolayer Coatings for Implanting Flexible Polymer Neural Probes in the Brain

Journal of Neuroscience Methods. Nov, 2009  |  Pubmed ID: 19666051

Penetrating microscale microelectrodes made from flexible polymers tend to bend or deflect and may fail to reach their target location. The development of flexible neural probes requires methods for reliable and controlled insertion into the brain. Previous approaches for implanting flexible probes into the cortex required modifications that negate the flexibility, limit the functionality, or restrict the design of the probe. This study investigated the use of an electronegative self-assembled monolayer (SAM) as a coating on a stiff insertion shuttle to carry a polymer probe into the cerebral cortex, and then the detachment of the shuttle from the probe by altering the shuttle's hydrophobicity. Polydimethylsiloxane (PDMS) and polyimide probes were inserted into an agarose in vitro brain model using silicon insertion shuttles. The silicon shuttles were coated with a carboxyl terminal SAM. The precision of insertion using the shuttle was measured by the percentage displacement of the probe upon shuttle removal after the probe was fully inserted. The average relative displacement of polyimide probes inserted with SAM-coated shuttles was (1.0+/-0.66)% of the total insertion depth compared to (26.5+/-3.7)% for uncoated silicon shuttles. The average relative displacement of PDMS probes was (2.1+/-1.1)% of the insertion depth compared to 100% (complete removal) for uncoated silicon shuttles. SAM-coated shuttles were further validated through their use to reliably insert PDMS probes in the cerebral cortex of rodents. This study found that SAM-coated silicon shuttles are a viable method for accurately and precisely inserting flexible neural probes in the brain.

The Insulation Performance of Reactive Parylene Films in Implantable Electronic Devices

Biomaterials. Oct, 2009  |  Pubmed ID: 19703712

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 degrees 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 10kHz and 70% greater at 1Hz 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.

Insertion of a Three Dimensional Silicon Microelectrode Assembly Through a Thick Meningeal Membrane

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2009  |  Pubmed ID: 19964007

There are many different needs for intraoperative mapping in both rodent as well as human brain. Whether the goal of the procedure is for epileptic mapping, removal of cancerous tissue, mapping the motor and sensory cortices, or understanding the underlying neural networks within the brain, dense three-dimensional electrode arrays are necessary. In this study, we outlined and validated thicker silicon probe designs for use in intracortical mapping applications. Multiple shank and electrode site configurations were implanted successfully through rat dura as a model for human pia, and all devices maintained the electrical functionality necessary for electrophysiological mapping applications.

Validation of a Novel Three-dimensional Electrode Array Within Auditory Cortex

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2009  |  Pubmed ID: 19964572

Three-dimensional electrode arrays have a variety of potential applications in the fields of both intracortical mapping as well as basic research studies designed to characterize and understand the physiology of the brain. While higher channels counts are desired in brain-machine interface applications, the ability to analyze synchronous data from multiple cortical locations, including various depths is pivotal to fully mapping the underlying neurophysiology of sensory cortices. Within this study, we present a proof of concept validation of a 3D probe technology consisting of 16 silicon shanks in a 4x4 grid arrangement with four electrode sites per shank. This 3D array has been implanted in a rat primary auditory cortex and electrophysiological data are presented showing the utility of electrode sites spanning multilateral cortical space as well as cortical depth.

Conducting-polymer Nanotubes Improve Electrical Properties, Mechanical Adhesion, Neural Attachment, and Neurite Outgrowth of Neural Electrodes

Small (Weinheim an Der Bergstrasse, Germany). Feb, 2010  |  Pubmed ID: 20077424

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.

Development of Closed-loop Neural Interface Technology in a Rat Model: Combining Motor Cortex Operant Conditioning with Visual Cortex Microstimulation

IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. Apr, 2010  |  Pubmed ID: 20144922

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.

In Vivo Electrical Conductivity Across Critical Nerve Gaps Using Poly(3,4-ethylenedioxythiophene)-coated Neural Interfaces

Plastic and Reconstructive Surgery. Dec, 2010  |  Pubmed ID: 20700080

Bionic limbs require sensitive, durable, and physiologically relevant bidirectional control interfaces. Modern central nervous system interfacing is high risk, low fidelity, and failure prone. Peripheral nervous system interfaces will mitigate this risk and increase fidelity by greatly simplifying signal interpretation and delivery. This study evaluates in vivo relevance of a hybrid peripheral nervous system interface consisting of biological acellular muscle scaffolds made electrically conductive using poly(3,4-ethylenedioxythiophene).

An Alginate Hydrogel Dura Mater Replacement for Use with Intracortical Electrodes

Journal of Biomedical Materials Research. Part B, Applied Biomaterials. Nov, 2010  |  Pubmed ID: 20878928

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.

Conducting Polymers on Hydrogel-coated Neural Electrode Provide Sensitive Neural Recordings in Auditory Cortex

Acta Biomaterialia. Jan, 2010  |  Pubmed ID: 19651250

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.

Investigation of the Material Properties of Alginate for the Development of Hydrogel Repair of Dura Mater

Journal of the Mechanical Behavior of Biomedical Materials. Jan, 2011  |  Pubmed ID: 21094477

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 CaCl(2) 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 CaCO(3) is sufficient for tissue replacement in large dural defects.

Poly(3,4-ethylenedioxythiophene) (PEDOT) Polymer Coatings Facilitate Smaller Neural Recording Electrodes

Journal of Neural Engineering. Feb, 2011  |  Pubmed ID: 21245527

We investigated using poly(3,4-ethylenedioxythiophene) (PEDOT) to lower the impedance of small, gold recording electrodes with initial impedances outside of the effective recording range. Smaller electrode sites enable more densely packed arrays, increasing the number of input and output channels to and from the brain. Moreover, smaller electrode sizes promote smaller probe designs; decreasing the dimensions of the implanted probe has been demonstrated to decrease the inherent immune response, a known contributor to the failure of long-term implants. As expected, chronically implanted control electrodes were unable to record well-isolated unit activity, primarily as a result of a dramatically increased noise floor. Conversely, electrodes coated with PEDOT consistently recorded high-quality neural activity, and exhibited a much lower noise floor than controls. These results demonstrate that PEDOT coatings enable electrode designs 15 µm in diameter.

Novel Multi-sided, Microelectrode Arrays for Implantable Neural Applications

Biomedical Microdevices. Jun, 2011  |  Pubmed ID: 21301965

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.

Use of a Bayesian Maximum-likelihood Classifier to Generate Training Data for Brain-machine Interfaces

Journal of Neural Engineering. Aug, 2011  |  Pubmed ID: 21654038

Brain-machine interface decoding algorithms need to be predicated on assumptions that are easily met outside of an experimental setting to enable a practical clinical device. Given present technological limitations, there is a need for decoding algorithms which (a) are not dependent upon a large number of neurons for control, (b) are adaptable to alternative sources of neuronal input such as local field potentials (LFPs), and (c) require only marginal training data for daily calibrations. Moreover, practical algorithms must recognize when the user is not intending to generate a control output and eliminate poor training data. In this paper, we introduce and evaluate a Bayesian maximum-likelihood estimation strategy to address the issues of isolating quality training data and self-paced control. Six animal subjects demonstrate that a multiple state classification task, loosely based on the standard center-out task, can be accomplished with fewer than five engaged neurons while requiring less than ten trials for algorithm training. In addition, untrained animals quickly obtained accurate device control, utilizing LFPs as well as neurons in cingulate cortex, two non-traditional neural inputs.

Theoretical Analysis of Intracortical Microelectrode Recordings

Journal of Neural Engineering. Aug, 2011  |  Pubmed ID: 21775783

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.

Microscale Electrode Implantation During Nerve Repair: Effects on Nerve Morphology, Electromyography, and Recovery of Muscle Contractile Function

Plastic and Reconstructive Surgery. Oct, 2011  |  Pubmed ID: 21921739

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.

Polarity of Cortical Electrical Stimulation Differentially Affects Neuronal Activity of Deep and Superficial Layers of Rat Motor Cortex

Brain Stimulation. Oct, 2011  |  Pubmed ID: 22032738

Cortical electrical stimulation (CES) techniques are practical tools in neurorehabilitation that are currently being used to test models of functional recovery after neurologic injury. However, the mechanisms by which CES has therapeutic effects, are not fully understood.