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Introduction: Intradural spinal cord stimulation (SCS) may offer significant therapeutic benefits for those with intractable axial and extremity pain, visceral pain, spasticity, autonomic dysfunction and related disorders. A novel intradural electrical stimulation device, limited by the boundaries of the thecal sac, CSF and spinal cord was developed to test this hypothesis. In order to optimize device function, we have explored finite element modeling (FEM). Methods: COMSOL®Multiphysics Electrical Currents was used to solve for fields and currents over a geometric model of a spinal cord segment. Cathodic and anodic currents are applied to the center and tips of the T-cross component of the electrode array to shape the stimulation field and constrain charge-balanced cathodic pulses to the target area. Results: Currents from the electrode sites can move the effective stimulation zone horizontally across the cord by a linear step method, which can be diversified considerably to gain greater depth of penetration relative to standard epidural SCS. It is also possible to prevent spread of the target area with no off-target action potential. Conclusion: Finite element modeling of a T-shaped intradural spinal cord stimulator predicts significant gains in field depth and current shaping that are beyond the reach of epidural stimulators. Future studies with in vivo models will investigate how this approach should first be tested in humans.

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

Background: 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. Objective: In this study, we investigated the effects of CES on unit activity of different neuronal elements in layers of rat primary motor cortex after the offset of stimulation. We evaluated the effects of monopolar CES pulse polarity (anodic-first versus cathodic-first) using various stimulation frequencies and amplitudes on unit activity after stimulation. Methods: A penetrating single shank silicon microelectrode array enabled us to span the entirety of six layer motor cortex allowing simultaneous electrophysiologic recordings from different depths after monopolar CES. Neural spiking activity before the onset and after the offset of CES was modeled using point processes fit to capture neural spiking dynamics as a function of extrinsic stimuli based on generalized linear model methods. Results: We found that neurons in lower layers have a higher probability of being excited after anodic CES. Conversely, neurons located in upper cortical layers have a higher probability of being excited after cathodic stimulation. The opposing effects observed following anodic versus cathodic stimulation in upper and lower layers were frequency- and amplitude-dependent. Conclusions: The data demonstrates that the poststimulus changes in neural activity after manipulation of CES parameters changes according to the location (depth) of the recorded units in rat primary motor cortex. The most effective pulse polarity for eliciting action potentials after stimulation in lower layers was not as effective in upper layers. Likewise, lower amplitudes and frequencies of CES were more effective than higher amplitudes and frequencies for eliciting action potentials. These results have important implications in the context of maximizing efficacy of CES for neurorehabilitation and neuroprosthetic applications.

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Objective. Cortical electrical stimulation (CES) has been used extensively in experimental neuroscience to modulate neuronal or behavioral activity, which has led this technique to be considered in neurorehabilitation. Because the cortex and the surrounding anatomy have irregular geometries as well as inhomogeneous and anisotropic electrical properties, the mechanism by which CES has therapeutic effects is poorly understood. Therapeutic effects of CES can be improved by optimizing the stimulation parameters based on the effects of various stimulation parameters on target brain regions. Approach. In this study we have compared the effects of CES pulse polarity, frequency, and amplitude on unit activity recorded from rat primary motor cortex with the effects on the corresponding local field potentials (LFP), and electrocorticograms (ECoG). CES was applied at the surface of the cortex and the unit activity and LFPs were recorded using a penetrating electrode array, which was implanted below the stimulation site. ECoGs were recorded from the vicinity of the stimulation site. Main results. Time–frequency analysis of LFPs following CES showed correlation of gamma frequencies with unit activity response in all layers. More importantly, high gamma power of ECoG signals only correlated with the unit activity in lower layers (V–VI) following CES. Time–frequency correlations, which were found between LFPs, ECoGs and unit activity, were frequency- and amplitude-dependent. Significance. The signature of the neural activity observed in LFP and ECoG signals provides a better understanding of the effects of stimulation on network activity, representative of large numbers of neurons responding to stimulation. These results demonstrate that the neurorehabilitation and neuroprosthetic applications of CES targeting layered cortex can be further improved by using field potential recordings as surrogates to unit activity aimed at optimizing stimulation efficacy. Likewise, the signatures of unit activity observed as changes in high gamma power in ECoGs suggest that future cortical stimulation studies could rely on less invasive feedback schemes that incorporate surface stimulation with ECoG reporting of stimulation efficacy.

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

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.

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

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

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

Electrocorticogram (ECoG) recordings of the 6-hydroxydopamine (6-OHDA)-lesioned parkinsonian rat have shown an increase in the power of cortical beta-band (15-30 Hz) oscillations ipsilateral to the lesion. The power of these oscillations is decreased with dopamine agonist administration. Here, we demonstrate that stimulation of an electrode implanted in the subthalamic nucleus alters the power of cortical beta and gamma oscillations in 6-OHDA-lesioned animals. These alterations are dependent on stimulation frequency, charge, and amplitude/pulse width. Oscillations were significantly reduced during 200- and 350-Hz stimulation. A minimum charge of 4 nC was required to elicit a reduction in oscillation power. A number of amplitude and pulse width combinations that reached 4 nC were tested; it was found that only the combinations of 33 microA/120 micros and 65 microA/60 micros significantly reduced cortical oscillations. The reduction in beta/gamma oscillation power due to deep brain stimulation (DBS) was consistent with a significant reduction in the animals' rotational behavior, a typical symptom of parkinsonism in the rat. A significant shift from high beta to low gamma was observed in the peak frequencies of ECoG recordings while animals were at rest versus walking on a treadmill. However, DBS exhibited no differential effect on oscillations between these two states. EEG recordings from rodent models of DBS may provide surrogate information about the neural signatures of Parkinson's disease relative to the efficacy of DBS.

Neural prosthetics capable of recording or stimulating neuronal activity may restore function for patients with motor and sensory deficits resulting from injury or degenerative disease. However, overcoming inconsistent recording quality and stability in chronic applications remains a significant challenge. A likely reason for this is the reactive tissue response to the devices following implantation into the brain, which is characterized by neuronal loss and glial encapsulation. We have developed a neural stem cell-seeded probe to facilitate integration of a synthetic prosthesis with the surrounding brain tissue. We fabricated parylene devices that include an open well seeded with neural stem cells encapsulated in an alginate hydrogel scaffold. Quantitative and qualitative data describing the distribution of neuronal, glial, and progenitor cells surrounding seeded and control devices is reported over four time points spanning three months. Neuronal loss and glial encapsulation associated with cell-seeded probes were mitigated during the initial week of implantation and exacerbated by six weeks post-insertion compared to control conditions. We hypothesize that graft cells secrete neuroprotective and neurotrophic factors that effect the desired healing response early in the study, with subsequent cell death and scaffold degradation accounting for a reversal of these results later. Applications of this biohybrid technology include future long-term neural recording and sensing studies.

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.

There are many different needs for intraoperative mapping in both rodent as well as human situations. 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.

Extracellular spike discharges were recorded from ensembles of up to five neurons simultaneously in the DCN of guinea pig using solid-state, thin-film, multichannel electrodes having up to five recording sites spanning up to 600 microns. Responses from 73 unit pairs were collected of which 54 had both units responding to pseudorandom wideband noise stimulation. Shared-stimulus driving was present in 78% (42/54) of the unit pairs and could be attributed to an overlap in their spectral sensitivities. Effective connectivity was indicated for 87% (47/54) of the unit pairs. Wideband noise proved more useful than tonebursts for investigating shared-stimulus driving and connectivity because it evoked widespread, but not overly synchronous, responses in the ensembles.

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.

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.

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 100μm 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). Information analysis of LFPs was conducted using a non- parametric clustering algorithm that estimated the statistical similarity of LFP frequency components associated with leftward and rightward movements using data from all layers of the rat primary motor cortex. Our findings suggest that the superficial layers of the motor cortex may be optimal for determining the movement direction from LFPs. We also provide evidence, using current source density (CSD) analysis, that the better decoding may be due to the synaptic activity in the upper layers.

Neuromotor prostheses (NMPs) seek to replace motor functions in paralyzed humans by controlling external devices directly from recording contacts placed within the brain (in effect, bypassing the damaged neural tissue). Studies to date have focused on cortical areas for NMP control, but deeper brain structures have also been implicated in generating motor commands. Recent studies combining non-invasive brain computer interface (BCI) experiments with functional brain imaging have revealed that the hemodynamic response related to activity of the Basal Ganglia (BG) increases significantly during BCI control. The BG has long been theorized to be involved in the selection of motor actions in the neocortex, and may be an ideal location for a discrete state NMP. In this report, we investigate the directional information contained in the firing rates of cells within the nuclei of the BG. Four Long-Evans rats performed a directional nose poke task while action potentials were recorded from 21 drivable tetrodes. Our preliminary analysis has identified 16 candidate interneurons and 8 primary cells from properties of the extracellular waveforms, and has determined the amount of directional information in each cell. Using an unsupervised classification decoder of the firing rates in the BG, we could predict the animal's movement direction correctly in >80% of the trials. We further analyzed the cell ensemble decoding and found that the proposed interneuron's directional information peaked ~100-175ms before the projection cells. The fast spiking interneurons of the striatum may be an important control source for NMPs as these cells are thought to play a large role in the selection of actions.

While the development of silicon-substrate microelectrode arrays has enabled chronic recording of single unit activity from multiple neurons simultaneously, accurate interpretation of the signals depend on the anatomical placement of the electrodes. Toward this end, this paper develops an in vivo method for identifying the placement of electrodes based on laminar analysis of ketamine-xylazien-induced field potential oscillations in rat motor cortex. The proposed method is based on finding the polarity reversal in laminar oscillations which is reported to appear in upper part of layer V in laminar High Voltage Spindles (HVSs) of rat cortical column. Analysis of histological images showed a 21 mum error in the estimate of the polarity reversal depth compared to the expected range (850-1050 mum). One out of the four rats did not undergo a phase reversal. Histology verified that the electrode was placed deeper than 1050 jim. We propose that this method can be used to determine an estimate of laminar electrodes implanted in rat motor cortex

Developments of the past decades have shown it is possible to decode and extract control signals directly from the brain for use in neuromotor prosthetics. Currently, there is a push towards developing closed loop interface systems. Here we describe our early results in a rat model of a sensory/motor neurophysiological feedback control system. Traditional operant conditioning techniques historically train an animal to increase or decrease the occurrence of a behavior in response to a stimulus using various types of reinforcement. Here we demonstrate a rat performing an operant conditioning task with the modification that the rat's behavioral output and stimulus input are accessed via direct electrical connections with the brain. Our preliminary results here show a rat successfully trained to modulate the firing rates of its motor cortex in response to intra-cortical microstimulation of the visual cortex.

Sharks swimming in the open ocean represent impressive examples of biological underwater sensor systems. Their chemical, electrical, and acoustic senses are finely tuned to survival in a complex, dynamic, and dangerous environment. While shark behavior and physiology is gaining increasing attention by marine biologists, the shark nervous system remains largely unexplored. However, it is the nervous system that holds an important key for understanding their sensory and motor acuities, and how this translates to behavior. The primary goal of this project was to develop an innovative implantable neural interface technology that would begin to pave the way for researchers to interface with highly specific targets in the nervous system of swimming sharks to monitor (record) and stimulate (write) neural activity. This project was focused at developing leading-edge neurotechnologies, MEMS technologies, and electronics into novel implantable neural interfaces in freely swimming sharks in order to investigate neural coding associated with sensory processing and natural behavior.

Electrocorticogram (ECoG) recordings of the 6-OHDA lesioned rat have shown an increase in the power of beta (15-30 Hz) oscillatory frequency on the lesioned side of the brain which reduces with dopamine agonist administration. Here, we were able to demonstrate that implantation and stimulation of an electrode at certain physiologic parameters in the subthalamic nucleus was able to modify the power of the beta oscillations. By measuring ECoG recordings, a deep brain stimulation (DBS) device may be able to vary its parameters to achieve a reduction in p power similar to that seen with medication.

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.

Brain Machine Interfaces (BMIs) are emerging as an important research area in clinical therapy. A large range of potential BMI control signals can be found in the brain. In increasing order of volume of brain tissue being sampled, these signal includes recordings of electric discharges from multi unit activity (MUA), summed population activity of thousands of neurons via local field potentials (LFPs), and electrical activity recorded from either the surface of the brain via electrocorticograms (ECoGs) or the surface of the scalp via electroencephalograms (EEGs). While each of these signals have been studied separately, it has been difficult to compare the potential that each signal has for general prosthetic control across studies. Information theory has been proposed as an abstract measurement to bridge this gap, however the maximum information rates of any experiment is limited by the parameters defined by that experiment (e.g. inter-trial interval length, number of targets). Here we propose a different measure of information, which we call information capacity, which measures the maximum possible information rate that a signal can provide. An advantage of measuring information capacity is that it can readily be compared between different signals and different tasks. We show how to calculate information capacity making linear Gaussian assumptions, and we discuss more general possibilities. We present a case study involving a rat BMI task involving either MUA or LFP signals.

Control of prosthetic devices is possible via extra-cellular recordings from cortical neurons. Many of the current cortical control paradigms consist of analyzing the relationship between cortical activity and measured arm movements, and then using this known relationship to map cortical activity to similar prosthetic arm movements. However, measured arm movements are not feasible for amputees or patients with mobility limitations hindering their ability to perform such movements. Here we explore an alternative approach using a rat model in which subjects learn prosthesis control via an adaptive decoding filter that adjusts to the modulation patterns recorded from neurons in the motor cortex. Our methodology takes into account the ability of a subject to learn an effective response strategy in conjunction with online filter adaptation. A modified Kalman filter is demonstrated to "co-adapt" by training on past periods of significant modulation during expected prosthetic device movement. Feedback pertinent to completing the cortical task is given to aid the animal in adopting a response strategy maximizing reward. One subject was able to perform the task consistently above chance after 2 days (4 sessions) of training.

The electrical stapedius reflex (ESR) threshold, detected by eardrum acoustic impedance change, is strongly correlated with cochlear implant recipients' behavioral comfort levels. However reports suggest acoustic impedance changes are not detectable in 30-40% of patients. The goals of this study were to develop an animal model and investigate the characteristics of the stapedius muscle electromyogram (SEMG) elicited by a cochlear implant, as an alternative measure of ESR activation. Bipolar tungsten micro wire electrodes recorded the SEMG signal from the stapedius muscle of 6 rats. The cochlea was implanted with a multichannel intracochlear electrode that delivered biphasic electrical pulses. Maximum SEMG potentials were 20-500 /spl mu/V (mean: 174 /spl mu/V) or 8-42 dB SNR (mean: 24 dB). The dynamic range of the responses that reached saturation were approximately 10 dB, with threshold inversely dependent on pulse-width and electrode separation. The electrical brainstem response (EABR) threshold was 5.6 dB lower than the ESR threshold on average, but the standard deviation was relatively high (2.4 dB), suggesting that these two signals could provide independent information for objective cochlear implant fitting. Post-operative SEMGs were recorded in several animals; including one animal for up to 63 days. The results suggest the overall feasibility of the approach for objective cochlear implant fitting.

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.

� 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.

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.

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.

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.