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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

The neocortex is a six-layered tissue consisting of different cell types. How does unit activity in the different layers of the motor cortex relate to movement? Does implantation in a particular layer improve direction decoding ability for a neuroprosthetic device? We simultaneously recorded unit activity in different layers of the rat motor cortex using chronic multi-site silicon electrodes. We used a combination of histology and electrophysiological signatures of Local Field Potentials (LFPs) to accurately localize the electrode sites in the different layers of the cortex. We analyzed 142 units from two animals and found that 40 units (28%) in Layers II to V showed significant modulation with respect to movement. Of these units that showed significant modulation, 9/20 (45%) of units in Layers II/III encoded directional information as compared to 15/19 (79%) of the units in Layers IV/V. These preliminary results suggest that units in Layers IV/V relatively contain more directional information than other layers of the cortex.