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� Abstract—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 (�1 = 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.

This paper presents a neural signal processing ASIC based on discrete wavelet transform (DWT). The recorded neural signals from 256 channels are analyzed by fast DWT algorithm with special ALUs, then, compressed by run-length encoders (RLE). The processed data are delivered through RF links and reconstructed in a host receiver. This design operates at 200 MHz clock with 2.5 V and was implemented with TSMC 0.25 mum technology. Recorded neural data test shows 1:89:3 (1.12%) compression rate and perfect in-band noise rejection

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.

Intracortical microelectrodes currently have the greatest potential for achieving a functional neural prosthesis in patients with neurodegenerative diseases or spinal cord injury. Device efficacy is lacking in long-term performance as seen in both chronological histology and biopotential recording studies.Some researchers have shown that small single polymer fibers (less than 7-μm diameter) do not induce an encapsulation layer in the rat subcutis so we have extended this concept to neural probe design. In this experiment we investigated the brain-tissue response of polymer probes with 4-μm feature sizes that are capable of withstanding insertion forces when penetrating the rat neocortex. This polymer probe has both a stiff penetrating shank (70-μm by 42-μm) and fine polymer structures (4-μm by 5-μm) that extend laterally from the shank. Our testing verifies that despite a flexible substrate and small dimensions, these devices are mechanically robust and practical as neural probes. We developed a microfabrication process using SU-8 and parylene to create the relatively thick probe shank and thin lateral arms.In vivo testing was conducted on seven Sprague-Dawley rats. These parylene devices were chronically implanted in the motor cortex for 4-weeks and then imaged using fluorescence microscopy. Cellular encapsulation and neuronal loss were assessed using a Hoechst counterstain and the immunomarker NeuN (neuronal nuclei).The tissue reactivity immediately around the fine-feature structures is greatly reduced, showing mild cell encapsulation (90±68% increase) relative to the probe shank (460±320% increase). Neuronal loss was only (21±25%) out to 25-μm relative to significant loss around the probe shank (47±19%). Additionally, laminin+, fibronectin+, and Ox42+ tissue often showed greater intensity and thickness at the shank, indicating that the dense scar formation typical of cortical implants was mitigated around the fine lateral structure.These results suggest that using MEMS-based microfabrication to create sub-cellular structures will significantly reduce encapsulation, which should extend the longevity of neural probes. We also believe this concept could be beneficial to any implantable sensor capable of scaled geometries.

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.

We describe here a neurotrophic electrode designed to improve long-term reliability and signal-to-noise in a brain-device interface. Our electrode consists of a fine microwire inside a polyimide tube. The polyimide tube is filled with nerve growth factor (NGF) incorporated into a fibrin matrix. Our goal is to have a neurite grow into the tube. The close apposition between neurite and the recording wire should enhance signal-to-noise. The physical connection between device and tissue should improve reliability. We have implanted complete devices in 4 rats. Each rat gets a four-electrode device implanted in the barrel cortex of each hemisphere. Each electrode is filled with a different test substance. One control tube contains only saline, and another contains only the fibrin matrix. The other two electrodes in each array are filled with different concentrations of NGF. Once weekly following the implant, each rat is sedated, and electrical activity in each of the electrodes recorded. Electrodes in 5 of the 8 implants exhibited multi-unit spindling activity. A direct comparison of the amplitude of action potentials over time in each of the types of implants shows that the presence of NGF within the polyimide tube leads to an increase in action potential amplitude.

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.

An inductively powered 64-site current microstimulating system, Interestim-2B, with a modular architecture and minimal number of off-chip components has been developed for neural prosthesis applications. Interestim-2B can generate any arbitrary current waveform and supports a variety of monopolar and bipolar stimulation protocols. A common analog line provides access to each site potential, and exhausts residual stimulus charges. In situ site impedance measurement capability helps indicate the defective sites in chronic stimulations. This paper also summarizes some of the in vitro and in vivo experimental results using a 16-site implant.

Rejuvenation of iridium microelectrode sites, which involves applying a 1.5 V bias for 4 s, has been shown to reduce site impedances of chronically implanted microelectrode arrays. This study applied complex impedance spectroscopy measurements to an equivalent circuit model of the electrode-tissue interface. Rejuvenation was found to cause a transient increase in electrode conductivity through an IrO/sub 2/ layer and a decrease in the surrounding extracellular resistance by 85 /spl plusmn/ 1% (n=73, t-test p < 0.001) and a decrease in the immediate site resistance by 44 /spl plusmn/ 7% (n=73, t-test p

Advanced microfabrication processes, biomaterials, and systems technologies are enabling progressively more sophisticated devices to interface with the brain. In particular, microscale implantable neural probe systems have been developed to reliably stimulate and/or record populations of neurons for long periods of time. Our group has developed a silicon-based probe technology is effective for recording neural activity from neuronal populations for sustained time periods. In a recent study in rats, these probes consistently and reliably provided high-quality spike recordings over extended periods of time. These probes are being used to investigate and develop cortical neuroprostheses and brain-machine interface systems. This neural probe technology is currently being extended to include polymer substrates, chemical interfaces for drug delivery, advanced coatings for improved biocompatibility, and integrated electronics for wireless communication to the outside world.

Summary form only given. Next-generation neuroprostheses are likely to involve monitoring or stimulating selective regions of the brain to restore neurological function or treat disease. An enabling technology for these devices is a microscale implantable neural probe system that provides a reliable interface with the brain at the cellular level for long periods of time. We have developed a silicon-based probe technology that has proven to be effective for recording neural activity from neuronal populations for sustained time periods. This technology is currently being extended to include a combined chemical interface for drug delivery, advanced coatings for improved biocompatibility, and integrated electronics for wireless communication to the outside world.

Cortical recording devices hold promise for providing augmented control of neuroprostheses and brain-computer interfaces in patients with severe loss of motor function due to injury or disease. This paper reports on the preliminary in vitro and in vivo results of our microscale implantable neural interface (MINI) probe system. The MINI is designed to use proven components and materials with a modular structure to facilitate ongoing improvements as new technologies become available. This device takes advantage of existing, well-characterized Michigan probe technologies and combines them to form a multichannel, multiprobe cortical assembly. To date, rat, rabbit, and non-human primate models have been implanted to test surgical techniques and in vivo functionality of the MINI. Results demonstrate the ability to form a contained hydrostatic environment surrounding the implanted probes for extended periods and the ability of this device to record electrophysiological signals with high SNRs. This is the first step in the realization of a cortically-controlled neuroprosthesis designed for human applications.

Brain machine interface development typically falls into two arenas, invasive extracellular recording and non-invasive electroencephalogram recording methods. The relationship between action potentials and field potentials is not well understood, and investigation of interrelationships may improve design of neuroprosthetic control systems. Rats were trained on a motor learning task whereby they had to insert their noses into an aperture while simultaneously pressing down on levers with their forepaws; spikes, local field potentials (LFPs), and electrocorticograms (ECoGs) over the motor cortex were recorded and characterized. Preliminary results suggest that the LFP activity in lower cortical layers oscillates with the ECoG.

Electrochemical sensing with microelectrode arrays provides a means for monitoring neurotransmitter dynamics across multiple locations within a micro-scale region of brain tissue. Here we present a multi-modal neural probe design for concurrent recording of neurochemical and electrophysiological signals in vivo. Prior to implantation, platinum sites on each array underwent platinum-black electroplating and Nafion electropolymerization, which increased sensitivity to dopamine by 74% and decreased sensitivity to common interferents by at least 89%. In a series of three rats, we applied various electrochemical waveforms to platinum sites and monitored neural activity on adjacent iridium sites. We found that chronoamperometry and constant-potential amperometry did not alter firing rates at +0.25, +0.50, and +0.75 V. In addition, we have demonstrated multi-modal recordings of striatal neurons in response to medial forebrain bundle stimulation.

Traditional brain-machine interfaces have typically focused on methods that use rate-based codes as a source for control signals. Opposed to rate, timing of firing across different neurons and within each neuron could also provide information that can be used for controlling brain-machine interfaces or neuroprosthetic devices. Findings have indicated that synchronization of individual spike discharges may help serve the organization of cortical motor processes. We are investigating neural firing synchrony in the context of using it for real-time control for neuroprostheses systems. Our results with rats suggest that subjects can be trained to synchronize neural firing and increase unitary events i.e. spike coincidence patterns that are significantly above chance. Temporal coding methods could be used as additional or alternative cortical control signals for neuroprostheses and brain machine interfaces.

ALGEL/sup /spl reg// (Neural Intervention Technologies, Ann Arbor, MI) has shown promise as a biocompatible and mechanically stable material when used as a dural sealant. ALGEL provides a suitable interface between the brain surface and cortical neural implants to help attain long-term neural recordings for over one year in laboratory animals. This paper investigates whether the ALGEL can cause abnormal neural activity or seizures when placed in contact with the motor cortex. Sixteen rats underwent craniotomy procedures and ALGEL and its reactive component, calcium chloride, were placed in contact with the cortex. The response of the animals was evaluated with electroencephalography (EEG) and clinical monitoring of behavior during controlled anesthesia for up to two hours post-application. ALGEL was compared with tranexamic acid (tAMCA), a synthetic fibrinolysis inhibitor that has been shown to cause epileptic seizures. tAMCA, at a dose of 100 mg/ml, showed marked paroxymal brain activity with associated and distinct episodes of jerk-correlated convulsive behaviors. However, various applications of ALGEL on the rat cortex showed no abnormal EEG signals and no episodes of jerk-correlated convulsive behaviors. ALGEL appears to be a safe and effective dural sealant that can be used alone or in combination with neural implants.

The characterization of the performance of microfluidic devices in the brain is crucial for reliable in-vivo drug delivery applications. Understanding the properties of brain tissue surrounding the microfluidic device and the mechanical response to a bolus delivery is important for optimizing the delivery capabilities. This study investigates the viscoelastic response of brain tissue to a micro-scale fluid volume. It was determined that significant tissue pressure changes and tissue relaxation time constants could be measured accurately and were found to correlate with the displacement volume used for injection. This is an important finding in developing and optimizing MEMS based in-vivo fluid delivery systems.

We sought to assess the stability of ALGEL (Neural Intervention Technologies, Ann Arbor, MI) as an embolic agent in an animal model of a cerebral arteriovenous malformation (AVM). Swine cerebral AVM models were used to test the mechanical stability and biocompatibility of ALGEL as an occlusive agent in a pre-clinical study for up to 6 month survival. The swine cerebral AVM model included a carotid-jugular anastomosis to increase flow to the rete mirabile (RM), thereby simulating the pressure gradient and shunted blood flow of an AVM. ALGEL and the reactive component, calcium chloride, were injected through double-lumen microcatheters to form an RM occlusion in chronic swine models. ALGEL injection 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- and six-month survival results showed that the ALGEL remained a stable occlusive material. Histology results showed a minor bioactive response and encapsulation of ALGEL, thereby increasing the stability and effective occlusion of the embolization material. ALGEL appears to initiate a bioactive response to maintain a stable and long-term endovascular occlusion.

Construction of a brain-machine interface system for neuroprosthetic purposes is at the forefront of many current neural engineering thrusts. Due to recent breakthroughs in device technology and implantation techniques, a basic framework is now sufficiently developed to allow design of systems level interface strategies producing robust, scalable BMIs that adapt quickly to optimize information transfer at the interface. It is useful to develop brain-machine interface systems in a modular fashion, enabling individual component research and development. This study investigates cortical microstimulation as a mode of operation for a sensory encoding component of a brain-machine interface system. It has previously been shown that cortical stimulation of sensory cortical areas produces sensations. In this report we compare behavior induced by either natural auditory cues, or cortical microstimulation of the primary auditory cortex. Five rats were implanted with multi-channel microwire arrays in auditory cortex and required to discriminate cortical microstimulation separated by 1.75 mm. The behavior was compared to auditory discrimination of tones separated by four octaves. The microstimulation resulted in 17% faster response times across the five rats.

Advances in BioMBMS have provided researchers with the capabilities to look at a myriad of things with more detail and precision than ever before, and the brain is no exception to this. The brain is becoming more accessible and controllable on almost every level; the challenge lies in increasing the quality of the interface with the brain. To address this challenge, we must begin by optimizing to the best of our capabilities the implantable devices used. One method to help optimize these devices is to integrate active electronics on the microelectrode that will enhance the quality of the signals being extracted from brain. This paper describes a chronic silicon-substrate microelectrode with integrated analog-front end electronics capable of recording from nearby neurons in active and passive modes of operation. Six-channel 2-D arrays have been chronically implanted into barrel cortex of two rats and have recorded chronic unit activity with SNRs up to 8:1.

Continued studies with calcium alginate gel (ALGEL/spl reg/-Neural Intervention Technologies, Ann Arbor, MI) show promise as an aneurysm occlusion material. Controlled ALGEL delivery eliminates flow to aneurysms and, when combined with coils, can eliminate the potential for ALGEL outflow from wide-neck, high flow aneurysms. Several aneurysm sizes were cast in flexible resins to simulate side-wall and bifurcation aneurysms in an in vitro system. First, ALGEL was delivered to small neck aneurysms from a 3F dual-lumen microcatheter. Second, a minimal number of coils were delivered to wide-neck aneurysms to form a matrix structure. ALGEL was then delivered to fill the remaining aneurysm space. ALGEL completely and effectively filled both small-neck aneurysms and, when combined with coils, completely filled wide-neck, high-flow aneurysms and eliminated outflow. Mechanical testing of ALGEL compared shear resistance to estimated shears seen in vivo. The frequency dependence of the complex modulus was determined at multiple % shears. ALGEL exhibits adequate stability to resist typical in vivo blood flow and shear effects subjected on aneurysms. ALGEL's mechanical stability and effective occlusion, alone and in combination with coils, makes ALGEL a potentially novel candidate for treating a wide variety of aneurysms and other neurovascular lesions.

In vitro soak tests lasting over 400 days were performed on polyimide sieve electrodes (PI2611D) using a method that allows in situ measurement of the impedance and relative dielectric constant of polyimide or alternate polymers. It was found that following an initial period of change, both values stabilized after a period of about 100 days. The dielectric constant was measured at 1 kHz and found to increase by 18% over 406 days. A short-term comparison (23 days) between polyimide cured on a hotplate in air versus using an oven with N/sub 2/ was also performed. No difference could be seen between the 2 methods.

This paper summarizes ongoing efforts in our laboratory to develop next-generation implantable neuroprobe systems that have closely integrated chemical and electrical neural interfaces. The MEMS-based neuroprobe consists of a silicon or polymer substrate having multiple metal sites for electrical recording and/or stimulation and one or more microchannels for fluid delivery. A chronoamperometric chemical sensor is achieved by selectively coating metal sites with an ion selective membrane. This multifunctional neuroprobe system provides a novel technology for establishing chronic and controllable chemical and electrical interfaces to targeted areas of the brain and spinal cord.

The capability of sensing catecholamine fluctuations in the brain is useful to determine how neurostimulation - both chemical and electrical - can affect catecholamine release and uptake. Here we report preliminary results on two multichannel neural probes capable of sensing dopamine through chronoamperometry methods. With a 16-channel microelectrode array and five-channel Michigan puffer probe with a microfluidic channel, we found that a 5-cycle dip coating process of Nafion, an ion-selective polymer, optimized sensitivity to dopamine and selectivity over ascorbic acid. In addition, through fluorescent microscopy, we have shown the suitability of Nafion as a "biocompatible" material for chronically implanted microelectrode probes. These findings support the ongoing work to develop chronic implantable chemical sensors.

A chief concern in the pursuit of controlling a neuroprosthetic device using direct brain signals is the question of how many bits of information are achievable through a direct brain-machine interface (BMI) via implantable microelectrode devices. This experiment begins to address this issue with implementation of a simple, software based decoding algorithm that allows the brain to adapt to the rules imposed upon it, To test this algorithm, two chronic 16-channel Michigan silicon microelectrode arrays were implanted into the primary motor cortex of two rats to record simultaneous unit spike activity. The animals were trained to perform an auditory detection task by modulating the recorded cortical spike activity in a prescribed manner. Both non-adaptive and adaptive neural decoding algorithms were evaluated. With the implementation of a non-adaptive decoding algorithm, the rats' behavioral (cortical) responses plateaued at approximately 75% correct; however, with the implementation of an adaptive algorithm, the rats' behavioral responses relatively quickly increased to 91% correct. The neural recordings suggest that the brain is able to modulate detailed cortical responses in accordance with the prescribed operant conditioning rules.

Surgical techniques are a critical contributor to the level of success achieved with chronically implanted cortical neuroprosthetic devices. Many different factors contribute to the amount of irritation the tissue is exposed to from the implanted device. Factors include mechanical irritations, infectious pathogens, dural regrowth, etc. In this paper we describe a novel application of the hydrogel polymer, ALGEL/spl reg/ (Neural Intervention Technologies, Ann Arbor, MI), in conjunction with an implanted Michigan probe (CNCT, University of Michigan). This polymer contains many inherent properties that are beneficial to this type of procedure. Properties include: 1) ease of application, 2) biocompatibility, 3) exemplary mechanical properties, and 4) translucent clarity. We believe that ALGEL has been a large contributor to the high level of success achieved with our chronic electrode implantations.

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 /spl alpha/-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid, an excitatory neurotransmitter, at multiple locations in the inferior colliculus. A nondimensional parameter, Q/spl tilde/, 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/in/sup 2/ (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.

Construction of a direct brain-machine interface (BMI) for neuroprosthetic purposes is at the forefront of many current neural engineering thrusts. Due to recent breakthroughs in device technology and implantation techniques, a basic framework is now sufficiently developed to allow design of systems level interface strategies producing robust, scalable BMIs that adapt quickly to optimize information transfer at the interface. It has been postulated that knowledge of the underlying neural coding is mandatory for further BMI development. In this preliminary report we use an adaptive algorithm requiring limited knowledge of the underlying neural coding to allow naive rats implanted with Michigan silicon microelectrode arrays in motor cortex to perform a tone discrimination task via differential modulation of the recorded signals. One subject was able to perform the task consistently above chance, despite minor daily fluctuations in recording populations and signal quality. The brain rapidly changed response strategies to facilitate performance of the task, and the algorithm subsequently adapted to accommodate improved BMI operation.

The desire to perform chronic recordings from many channels in cortex is high among both neuroscientists and neural prosthesis researchers. The Michigan probe with integrated silicon ribbon cable has been used successfully for obtaining chronic cortical recordings in rodents. As these silicon devices are applied in larger animals and potentially in humans, however, a more mechanically robust, scalable system is required. Here we present a device that takes advantage of several existing, well-characterized technologies and methods and combines them to form a hybrid cortical assembly. The components of the assembly include thin-film multichannel silicon probes and polyimide cables that are electrically and mechanically coupled using thermocompression ball bonding. The resulting probe/cable assembly is low profile (

BioMEMS devices can be designed to provide viable neural interfaces for long-term, high-density, two-way communication with selected areas of cerebral cortex. Prototype thin-film polymer implantable microelectrode arrays were developed to extend the microelectrode design space in several ways, including enhanced flexibility, engineered surfaces and coatings, and new types of microchannels. Prototype MEMS silicon microdevices were developed as microsurgical tools for reliably inserting the flexible polymer electrodes into the cerebral cortex. Hybrid polymer microdevices were also developed for neural recording and stimulation combined with micro-drug delivery.

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.

A finite element model has been developed to investigate the theoretical relationship between changes in extracellular resistivity and electrical potential in a chronic extracellular recording scenario. The inputs to the model are experimental results obtained from chronic recording and complex impedance measurements in cerebral cortex of adult guinea pigs. Using the measured tissue-electrode impedance to set the resistivity in the model provides simulated extracellular potentials that are consistent with the measured spike amplitudes. In both the experimental and theoretical paradigms it was found that increased extracellular resistivity results in an increased potential at the recording electrode tip. Although the results of the two methods could not be directly correlated, they do suggest that a certain amount of variance can be accounted for by the increased resistivity values. The methods presented offer a powerful theoretical tool for understanding some of the factors, which may affect chronic extracellular recording stability.

A direct interface with motor cortical neurons could provide an optimal signal for controlling a neural prosthesis. In order to accomplish this, a real-time conversion of simultaneously recorded neural activity to an on-line command for movement is required. A system has been established to isolate the cellular activity of a group of cortical neurons and interpret their movement related information with a minimal delay. Data from a two-month simulation of this system is presented.

The cochlear nucleus (CN) transforms the spike-discharge activity of auditory-nerve fibers to form second-order sound representations. Onset units are one subclass of CN neurons and are notable for their response to changes in the synchrony of their high frequency auditory-nerve fiber inputs. The authors show that the mechanisms underlying this response can be used to inspire an algorithm for estimating the fundamental frequency of speech in background noise using standard Fourier-based methods.

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.

Self-organizing map (SOM) has been applied in many different fields of science and engineering. In this chapter it is shown how the SOM can be used to decode neural spike trains of an awake animal and associate external auditory stimuli with spike patterns of the brain. This chapter begins with an introduction of the SOM and highlights advantages of the SOM when compared to other multivariate statistical data analysis tools commonly used to analyze similar data sets. In this study, simultaneous multichannel recording from guinea pig auditory cortex is examined using the SOM to assess the effectiveness and potential of the SOM in neurophysiological studies.

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.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.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.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.

This paper describes a detailed protocol for obtaining chronic, multi-site unit recordings in cerebral cortex of awake animals for periods of three months or more. The protocol includes details for making relatively simple and inexpensive implantable multichannel electrodes that consist of arrays of separate microwires. The results reported in this paper suggest that a viable implant will have discriminable unit activity on about 80% of the electrodes, resulting in, on average, the simultaneous unit recording of upwards of 60 units during a daily recording session. The active electrodes during one recording session tend to remain active in subsequent recording sessions for several weeks. Using the methods described here, implants have been constructed which incorporate several different electrode materials, coatings, sizes, and electrode separation within a single array. These microwire electrode arrays provide the basic technology for obtaining unit recordings for several months. This provides a model system for studying biocompatibility of neural implants, which is a critical component for the development of neural implants that have an indefinite working span. Themes: Sensory Systems Topics: Auditory systems: central physiology

Octopus cells are one of the principal cell types in the mammalian posteroventral cochlear nucleus. These cells respond to the onset of a toneburst with a precisely timed spike followed by little, if any, sustained activity. While experimental studies have partially characterized the cell, the mechanisms of this onset response are not well understood. The present study involved a model-based investigation that analyzed the responses of a compartmental model of the octopus cell in terms of synaptic effectiveness and dynamic spike threshold. The simulations demonstrate that properties of the onset response (first-spike latency, temporal precision of the first spike, and sustained firing rate) can be predicted from the values of these cell properties for a wide range of model configurations. These relationships were further analyzed through the development of mathematical expressions for synaptic effectiveness and dynamic spike threshold. This computational analysis resulted in a relatively simple explanation of the onset response, as well as predictions of the responses of octopus cells to nontonal, complex stimuli.

We developed a biologically plausible, compartmental model of stellate cells in the cochlear nucleus (CN) to investigate the effects of synaptic distribution on spike activity using constant and amplitude-modulated (AM) tones. Differences in the spatial distribution of excitatory auditory nerve (AN) inputs and inhibitory non-cochlear inputs evoke a range of post-stimulus time histogram (PSTH) chopper responses from sustained to transient to onset. These simulations illustrate how intrinsic membrane properties and non-linear dendritic processing of AN inputs determine the temporal responses characteristic of stellate cells observed in PSTHs and modulation transfer functions (MTFs).

The cochlear nucleus (CN) is the gateway to the central auditory system. The auditory nerve branches and terminates in the CN forming separate tonotopic maps in each of the nucleus’s three subdivisions. Octopus cells are found exclusively in the posteroventral cochlear nucleus and project to the inferior colliculus. These cells are sensitive to physical properties of sound, such as frequency, intensity, and amplitude fluctuations, although their role in auditory processing is unknown. Over a 40 dB dynamic range, the octopus cell always fires an action potential at the onset of a pure tone and then fires randomly at much lower rates throughout the rest of the tone. This onset response has not yet been explained in terms of the cell’s known physiological and anatomical properties, which include a fast membrane, highly convergent primary afferent inputs, and few inhibitory inputs. A better understanding of the properties underlying this response will provide increased, quantitative insight into auditory processing.

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.

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 microns in diameter.

We describe a computational model of the Limulus lateral eye to investigate the relationship between the neural coding of the retina and the visual performance of the animal. The network model, implemented on the massively parallel Connection Machine, computes the firing rates of optic-nerve fibers for simulated visual scenes. Intensity-response functions computed for individual nerve fibers that project to the brain agree with experimental measurements. Responses computed for the entire array of retinal neurons show that moving targets enhance the modulation of optic-nerve activity.

Penetrating neural probe technologies allow investigators to record electrical signals in the brain. The implantation of probes causes acute tissue damage, partially due to vasculature disruption during probe implantation. This trauma can cause abnormal electrophysiological responses and temporary increases in neurotransmitter levels, and perpetuate chronic immune responses. A significant challenge for investigators is to examine neurovascular features below the surface of the brain in vivo. The objective of this study was to investigate localized bleeding resulting from inserting microscale neural probes into the cortex using two-photon microscopy (TPM) and to explore an approach to minimize blood vessel disruption through insertion methods and probe design. 3D TPM images of cortical neurovasculature were obtained from mice and used to select preferred insertion positions for probe insertion to reduce neurovasculature damage. There was an 82.8 +/- 14.3% reduction in neurovascular damage for probes inserted in regions devoid of major (5 microm) sub-surface vessels. Also, the deviation of surface vessels from the vector normal to the surface as a function of depth and vessel diameter was measured and characterized. 68% of the major vessels were found to deviate less than 49 microm from their surface origin up to a depth of 500 microm. Inserting probes more than 49 microm from major surface vessels can reduce the chances of severing major sub-surface neurovasculature without using TPM.