Search

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.

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

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.

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.

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.

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.

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

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

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.

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.

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.

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.

Introduction Technological advances in neural interfaces are providing increasingly more powerful “toolkits” of designs, materials, components, and integrated devices for establishing high-fidelity chronic neural interfaces. For a broad class of neuroscience studies, the primary

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.

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

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.

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

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.

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

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

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

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

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

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

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.