Spatiotemporal characteristics of neural activity in tibial nerves with carbon nanotube yarn electrodes.

BACKGROUND: Reliable interfacing with peripheral nervous system is essential to extract neural signals. Current implantable peripheral nerve electrodes cannot provide long-term reliable interfaces due to their mechanical mismatch with host nerves. Carbon nanotube (CNT) yarns possess excellent mechanical flexibility and electrical conductivity. It is of great necessity to investigate the selectivity of implantable CNT yarn electrodes. NEW METHOD: Neural interfaces were fabricated with CNT yarn electrodes insulated with Parylene-C. Acute recordings were carried out on tibial nerves of rats, and compound nerve action potentials (CNAPs) were electrically evoked by biphasic current stimulation of four toes. Spatiotemporal characteristics of neural activity and spatial selectivity of the electrodes, denoted by selectivity index (SI), were analyzed in detail. RESULTS: Conduction velocities of sensory afferent fibers recorded by CNT yarn electrodes varied between 4.25 m/s and 37.56 m/s. The SI maxima for specific toes were between 0.55 and 0.99 across seven electrodes. SIs for different CNT yarn electrodes are significantly different among varied toes. COMPARISON WITH EXISTING METHODS: Most single CNT yarn electrode with a ∼ 500 µm exposed length can be sensitive to one or two specific toes in rodent animals. While, it is only possible to discriminate two non-adjacent toes by multisite TIME electrodes. CONCLUSION: Single CNT yarn electrode exposed ∼ 500 µm showed SI values for different toes comparable to a multisite TIME electrode, and had high spatial selectivity for one or two specific toes. The electrodes with cross section exposed could intend to be more sensitive to one specific toe.

Blind source separation of peripheral nerve recordings.

Prosthetic devices can be controlled using signals recorded in parts of the body where sensation and/or voluntary movement have been retained. Although neural prosthetic applications have used single-channel recordings, multiple-channel recordings could provide a significant increase in useable control signals. Multiple control signals can be acquired from recordings of a single implant by using a multi-contact electrode placed over a multi-fasciculated peripheral nerve. These recordings can be separated to recover the individual fascicular signals. Blind source separation (BSS) algorithms have been developed to extract independent source signals from recordings of their mixtures. The hypothesis that BSS algorithms can recover individual fascicular signals from nerve cuff recordings at physiological signal-to-noise ratio (SNR approximately 3-10 dB) was investigated in this study using a finite-element model (FEM) of a beagle hypoglossal nerve with a flattening interface nerve electrode (FINE). Known statistical properties of fascicular signals were used to generate a set of four sources from which the neural signals recorded at the surface of the nerve with a multi-contact FINE were simulated. Independent component analysis (ICA) was then implemented for BSS of the simulated recordings. A novel post-ICA processing algorithm was developed to solve ICA's inherent permutation ambiguities. The similarity between the estimated and original fascicular signals was quantified by calculating their correlation coefficients. The mean values of the correlation coefficients calculated were higher than 0.95 (n = 50). The effects of the geometric layout of the FINE electrode and noise on the separation algorithm were also investigated. The results show that four distinct overlapping fascicular source signals can be simultaneously recovered from neural recordings obtained using a FINE with five or more contacts at SNR levels higher than 8 dB making them available for use as control signals.

Suppression of axonal conduction by sinusoidal stimulation in rat hippocampus in vitro.

Deep brain stimulation (DBS), also known as high frequency stimulation (HFS), is a well-established therapy for Parkinson's disease and essential tremor, and shows promise for the therapeutic control of epilepsy. However, the direct effect of DBS on neural elements close to the stimulating electrode remains an important unanswered question. Computational studies have suggested that HFS has a dual effect on neural elements inhibiting cell bodies, while exciting axons. Prior experiments have shown that sinusoidal HFS (50 Hz) can suppress synaptic and non-synaptic cellular activity in several in vitro epilepsy models, in all layers of the hippocampus. However, the effects of HFS on axons near the electrode are still unclear. In the present study, we tested the hypothesis that HFS suppresses axonal conduction in vitro. Sinusoidal HFS was applied to the alvear axon field of transverse rat hippocampal slices. The results show that HFS suppresses the alvear compound action potential (CAP) as well as the CA1 antidromic evoked potential (AEP). Complete suppression was observed as a 100% reduction in the amplitude of the evoked field potential for the duration of the stimulus. Evoked potential width and latency were not significantly affected by sinusoidal HFS. Suppression was dependent on HFS amplitude and frequency, but independent of stimulus duration and synaptic transmission. The frequency dependence of sinusoidal HFS is similar to that observed in clinical DBS, with maximal suppression between 50 and 200 Hz. HFS produced not only suppression of axonal conduction but also a correlated rise in extracellular potassium. These data provide new insights into the effects of HFS on neuronal elements, and show that HFS can block axonal activity through non-synaptic mechanisms.

Neural engineering--a new discipline for analyzing and interacting with the nervous system.

OBJECTIVES: The field of neural engineering focuses on an area of research at the interface between neuroscience and engineering. The area of neural engineering was first associated with the brain machine interface but is much broader and encompasses experimental, computational, and theoretical aspects of neural interfacing, neuroelectronics, neuromechanical systems, neuroinformatics, neuroimaging, neural prostheses, artificial and biological neural circuits, neural control, neural tissue regeneration, neural signal processing, neural modelling and neuro-computation. One of the goals of neural engineering is to develop a selective interface for the peripheral nervous system. METHODS: Nerve cuffs electrodes have been developed to either reshape or maintain the nerve into an elongated shape in order to increase the circumference to cross sectional ratio. It is then possible to place many electrodes around the nerve to achieve selectivity. This new cuff (flat interface nerve electrode: FINE) was applied to the hypoglossal nerve and the sciatic nerve in dogs and cats to estimate the selectivity of the interface. RESULTS: By placing many contacts close to the axons, three different types of selectivity were achieved: 1) The FINE could generate a high degree of stimulation selectivity as estimated by the individual fascicle recording. 2) Similarly, recording selectivity was also demonstrated and blind source algorithms were applied to recover the signals. 3) Finally, by placing arrays of electrodes along the nerve, small fiber diameters could be excited before large fibers thereby reversing the recruitment order. CONCLUSION: Taking advantage of the fact that nerves are not round but oblong or flat allows a novel design for selective nerve interface with the peripheral nervous system. This new design has found applications in many disorders of the nervous system such as bladder incontinence, obstructive sleep apnea and stroke.

CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy.

OBJECTIVES: To determine predictors of clinical relapse of cytomegalovirus (CMV) end-organ disease in a cohort of 17 HIV-infected patients with healed and treated CMV retinitis (CMVR) who responded to HAART with an increase in CD4 cell counts to above 70 cells/mm3 and discontinued CMV maintenance therapy (MT). DESIGN: Seventeen patients were monitored for reactivation of retinitis. The CD4 cell counts, HIV RNA and peripheral blood mononuclear cell (PBMC) lymphoproliferative assays to CMV at 3 month intervals were compared between patients with and without reactivation of CMVR. Positive lymphoproliferative responses were defined as a stimulation index of 3 or greater. RESULTS: Five out of 17 (29%) patients experienced a recurrence of CMVR a mean of 14.5 months after stopping CMV MT and between 8 days and 10 months after CD4 cell counts fell below 50 cells/mm3. Median CD4 cell counts and plasma HIV RNA at reactivation were 37 cells/mm3 and 5.3 log10 copies/ml. Three patients recurred at a previously active site of the retina, one had contralateral CMVR, and one a recurrence of retinitis and pancreatitis simultaneously. Mean lymphoproliferative responses to CMV were 2.4 in patients with reactivation versus 21.0 stimulation index (SI) in patients without reactivation (P= 0.01). A model incorporating four variables (CD4 cell counts and HIV RNA at maintenance discontinuation, highest CD4 cell count, nadir HIV RNA and median lymphoproliferative responses) identified correctly 88% of patients with and without reactivation. CONCLUSION: CMV disease recurs after virological and immunological failure of HAART if CD4 cell counts drop below 50. In this situation, anti-CMV agents should be resumed before clinical reactivation ensues, because of the risk of contralateral retinal involvement and systemic disease.

Chronic recordings of hypoglossal nerve activity in a dog model of upper airway obstruction.

The activity of the hypoglossal nerve was recorded during pharyngeal loading in sleeping dogs with chronically implanted cuff electrodes. Three self-coiling spiral-cuff electrodes were implanted in two beagles for durations of 17, 7, and 6 mo. During quiet wakefulness and sleep, phasic hypoglossal activity was either very small or not observable above the baseline noise. Applying a perpendicular force on the submental region by using a mechanical device to narrow the pharyngeal airway passage increased the phasic hypoglossal activity, the phasic esophageal pressure, and the inspiratory time in the next breath during non-rapid-eye-movement sleep. The phasic hypoglossal activity sustained at the elevated level while the force was present and increased with increasing amounts of loading. The hypoglossal nerve was very active in rapid-eye-movement sleep, especially when the submental force was present. The data demonstrate the feasibility of chronic recordings of the hypoglossal nerve with cuff electrodes and show that hypoglossal activity has a fast and sustained response to the internal loading of the pharynx induced by applying a submental force during non-rapid-eye-movement sleep.

Spiral nerve cuff electrode for recordings of respiratory output.

The feasibility of using the spiral nerve cuff electrode design for recordings of respiratory output from the hypoglossal (HG) and phrenic nerves is demonstrated in anesthetized, paralyzed, and artificially ventilated cats. Raw neural discharges of the HG nerve were analyzed in terms of signal-to-noise ratios and frequency spectra. The rectified and integrated moving average activity of the HG nerve had a peak value of 1.74 +/- 0.21 microV and a baseline value of 0.72 +/- 0.11 microV at elevated respiratory drive induced by increases in CO2 or oxygen deprivation when recorded with 10-mm-long cuffs. The frequency content of the HG electroneurogram extended from several hundred hertz to 6 kHz. Spiral nerve cuff recordings without desheathing of the nerve provided large enough signal-to-noise ratios that allowed them to be used as a measure of respiratory output and had much wider frequency bandwidths than the hook electrode preparations. A major advantage of the cuff electrode over the hook electrode was its mechanical stability, which significantly improved the reproducibility of the recordings both in terms of signal amplitudes and frequency contents.

Effects of applied currents on spontaneous epileptiform activity induced by low calcium in the rat hippocampus.

It is known that both applied and endogenous electrical fields can modulate neuronal activity. In this study, we have demonstrated that anodic current injections can inhibit spontaneous epileptiform events in the absence of synaptic transmission. Activity was induced with low-Ca2+ (0.2 mM) artificial cerebrospinal fluid (ACSF) and detected with a voltage threshold detector. At the onset of an event, a current was injected into the stratum pyramidale via a tungsten electrode positioned within 150 micron of the recording site. Data was recorded with a glass pipette electrode. The results show that spontaneous epileptiform activity can be fully suppressed by subthreshold anodic currents with an average amplitude of 3.9 microA and a minimum amplitude of 1 microA. In addition, we observed that some events could be blocked by current pulses with shorter durations than the duration of the event itself. The possibility that increased tissue resistance could contribute to the efficacy of the currents was tested by measuring the step-potential increase evoked by anodic current injections. The data show a significant increase in the amplitude of the evoked potential after introduction of a low-Ca2+ medium, suggesting that tissue resistance is increasing. These results indicate that low-amplitude, subthreshold current pulses are sufficient to block epileptiform activity in a low-Ca2+ environment. The increased tissue resistance induced by sustained exposure to a low-Ca2+ medium could contribute to the low current amplitudes required to block the epileptiform events.

Nonlinear dynamic properties of low calcium-induced epileptiform activity.

The analysis of the dynamic properties of epileptiform activity in vitro has led to a better understanding of the time course of neural synchronization and seizure states. Nonlinear analysis is thus potentially useful for the prediction of seizure onset. We have used nonlinear analysis methods to investigate the development of activity in the low calcium model of epilepsy in brain slices. This model is particularly interesting since neurons synchronize in the absence of synaptic transmission. The dynamic properties calculated from extracellular recordings of activity were used to analyze the transition to synchronous firing and their relation to neuronal excitability. The global embedding dimension, local dimension and the Lyapunov exponent were calculated from time segments corresponding to the onset, transition and fully developed stages of activity. The analysis was repeated for recordings made in the presence of various levels of DC electric fields to modulate neuronal excitability. The global and local dimensions did not change once activity was first initiated, even in the presence of the electric field. The maximum Lyapunov exponents increased during the onset of activity but decreased when the applied hyperpolarizing electric field was large enough to partially suppress the activity. These findings establish a relationship between neuronal excitability and the maximum Lyapunov exponent, and suggest that the Lyapunov exponent may be used to distinguish between various states of the neural network and might be important in seizure prediction and control.

Prediction of neural excitation during magnetic stimulation using passive cable models.

A method for predicting neural excitation during magnetic stimulation using passive cable models has been developed. This method uses the information of the threshold capacitor voltage for magnetic stimulation coils to determine the equivalent excitation thresholds for the passive transient (PT) and passive steady-state (PSS) cable models as well as for the activating function. The threshold values for the PT, PSS models, and the activating function vary only with the pulsewidth of the stimulus for a variety of coils at different locations and orientations. Furthermore, the excitation threshold for the PSS model is also independent of axon diameter and best fitted to a simple mathematical function. By comparing the transmembrane potential of the PSS model with the corresponding threshold, the prediction of excitation during magnetic stimulation can be made. Similarly, it is also possible to predict excitation using the PT model and the activating function with the corresponding thresholds provided. By taking advantage of the weighted pulsewidth, this method can even predict the excitation for stimuli with various waveforms, greatly simplifying the determination of neural excitation for magnetic stimulation.

Nonlinear parameter estimation by linear association: application to a five-parameter passive neuron model.

Linear associative memories (LAM) have been intensely used in the areas of pattern recognition and parallel processing for the past two decades. Application of LAM to nonlinear parameter estimation, however, has only been recently attempted. The process consists in converting the nonlinear function in the parameters into a set of linear algebraic equations. The nature of the linearized system and the factors influencing the accuracy of the parameter estimates have not yet been fully investigated. In this paper, LAM is applied to a nonlinear five-parameter model of the neuron. Ill-conditioning, which is often exhibited in LAM, is treated with the method of regularization as well as by the singular value decomposition (SVD). Simulation results indicate that the parameters estimated by LAM exhibit a remarkable robustness against additive white noise in comparison with the classical gradient optimization technique. Moreover, it is shown that regularization can be superior to SVD under certain conditions. Our results suggest that LAM can be used both as a noise reduction technique and as a stand-alone nonlinear parameter estimation algorithm. The comparison between LAM and a gradient technique show that, for this estimation problem, the LAM method can give more reliable estimates. Further improvements in estimation quality may still be achieved by the use of other forms of regularizing functions.

Theoretical study of magnetic field of current monopoles in special volume conductor using symmetry analysis.

We derive a formula for the magnetic field outside volume conductors having axial symmetry with radial and axial symmetrically distributed source currents. The magnetic field is shown to have components only along the cylindrical polar angle direction and its magnitude to depend only on the topological structure of the volume conductor and the location of the source current. With this formula, the magnetic field generated by the volume current of a current monopole within and on the symmetrical axis of several volume conductors (such as semi-infinite volume, infinite slab, sphere, infinite cylinder, semi-infinite cylinder, finite cylinder, prolate spheroid, and oblate spheroid) is shown to be equivalent to the magnetic field generated by a line current calculated using the Biot-Savart's law. In the first three volume conductors, the monopole solution of the magnetic field allows the calculation of magnetic fields generated by arbitrarily distributed (and balanced for finite volume conductors) current monopoles.

Analysis of magnetic stimulation of a concentric axon in a nerve bundle.

In this paper, we present an analysis of magnetic stimulation of an axon located at the center of a nerve bundle. A three-dimensional axisymmetric volume conductor model is used to determine the transmembrane potential response along an axon due to induced electric fields produced by a toroidal coil. We evaluate four such models of an axon located in: 1) an isotropic nerve bundle with no perineurium, 2) an anisotropic nerve bundle without a perineurium, 3) an isotropic nerve bundle surrounded by a perineurium, and 4) an anisotropic nerve bundle surrounded by a perineurium. The transmembrane polarization computed along an axon for the above four models is compared to that for an axon located in an infinite homogeneous medium. These calculations indicate that a nerve bundle with no sheath has little effect on the transmembrane potential. However, the presence of a perinerium around the nerve bundle and anisotropy in the bundle significantly affects the shape of the transmembrane response. Therefore, during magnetic stimulation, nerve bundle anisotropy and the presence of perineurium must be taken into account for calculation of stimulus intensities for threshold excitation.

Parameter estimation by reduced-order linear associative memory (ROLAM).

In a series of papers we have shown that nonlinear parameter estimation by linear association provides accurate estimates of the parameters in complex systems described by nonlinear differential equations even in the presence of additive white noise of considerable power. The technique is based on linearly associating the system's output with a set of parameter values spanning the region of interest. When an actual output is measured, the system's unknown parameters could be estimated by a matrix inversion. The size of the inverted matrix, being equal to the length of the output vector, poses a limiting factor upon the generalization of the technique. In this paper we propose a modification which requires the inversion of a matrix whose dimension equals the number of model parameters. The modified version is called reduced-order associative memory (ROLAM). The technique is applied to two complex lumped-parameter nonlinear models: the Van der Pol relaxation oscillator and the passive neuron model of the granule cells. Results validate ROLAM as a parameter-estimation tool which is especially suited in cases where the number of parameters is large, the number of samples in the observation signal is high, or when on-line parameter estimation is required. It is also shown that ROLAM provides an optimal parameter estimate in the special case of single-parameter nonlinear models.

A 3-D differential coil design for localized magnetic stimulation.

A novel three-dimensional (3-D) differential coil has been designed for improving the localization of magnetic stimulation. This new coil design consists of a butterfly coil with two additional wing units and an extra bottom unit, both perpendicular to the plane of the butterfly coil. The wing units produce opposite fields to restrict the spread of induced fields while the bottom unit enhances the induced fields at the excitation site. The peak induced field generated by this new design is located at the center of the coil, providing an easy identification of the excitation site. The field localization of the new coil is comparable with that of much smaller coils but with an inductance compatible to current magnetic stimulators. Numerical computations based on the principles of electromagnetic induction and using a human nerve model were performed to analyze the induced fields and the stimulation thresholds of new coil designs. The localization of the coil design was assessed by a half power region (HPR), within which the magnitude of the normalized induced field is greater than 1/square root of 2. The HPR for a 3-D differential coil built is improved (decreased) by a factor of three compared with a standard butterfly coil. Induced fields by this new coil were measured and in agreement with theoretical calculations.

Toroidal coil models for transcutaneous magnetic stimulation of nerves.

A novel design of coils for transcutaneous magnetic stimulation of nerves is presented. These coils consist of a toroidal winding around a high-permeability material (Supermendur) core embedded in a conducting medium. Theoretical numerical calculations are used to analyze the effect of the design parameters of these coils, such as coil width, toroidal radius, conducting layer thickness and core transversal shape on the induced electric fields in terms of the electric field strength and distribution. Results indicate that stimulation of nerves with these coils has some of the advantages of both electrical and magnetic stimulation. These coils can produce localized and efficient stimulation of nerves with induced electric fields parallel and perpendicular to the skin similar to surface electrical stimulation. However, they retain some of the advantages of magnetic stimulation such as no risk of tissue damage due to electrochemical reactions at the electrode interface and less uncomfortable sensations or pain. The driving current is reduced by over three orders of magnitude compared to traditional magnetic stimulation, eliminating the problem of coil heating and allowing for long duration and high-frequency magnetic stimulation with inexpensive stimulators.

A generalized cable equation for magnetic stimulation of axons.

During magnetic stimulation, electric fields are induced both on the inside (intracellular region) and the outside (extracellular region) of nerve fibers. The induced electric fields in each region can be expressed as the sum of a primary and a secondary component. The primary component arises due to an applied time varying magnetic field and is the time derivative of a vector potential. The secondary component of the induced field arises due to charge separation in the volume conductor surrounding the nerve fiber and is the gradient of a scalar potential. The question, "What components of intracellular fields and extracellular induced electric fields contribute to excitation?" has, so far, not been clearly addressed. In this paper, we address this question while deriving a generalized cable equation for magnetic stimulation and explicitly identify the different components of applied fields that contribute to excitation. In the course of this derivation, we review several assumptions of the core-conductor cable model in the context of magnetic stimulation. It is shown that out of the possible four components, only the first spatial derivative of the intracellular primary component and the extracellular secondary component of the fields contribute to excitation of a nerve fiber. An earlier form of the cable equation for magnetic stimulation has been shown to result in solutions identical to three-dimensional (3-D) volume-conductor model for the specific configuration of an isolated axon in a located in an infinite homogenous conducting medium. In this paper, we extend and generalize this result by demonstrating that our generalized cable equation results in solutions identical to 3-D volume conductor models even for complex geometries of volume conductors surrounding axons such as a nerve bundle of different conductivity surrounding axons. This equivalence in the solutions is valid for several representations of a nerve bundle such as anisotropic monodomain and bidomain models.

Improved nerve cuff electrode recordings with subthreshold anodic currents.

A method has been developed for improving the signal amplitudes of the recordings obtained with nerve cuff electrodes. The amplitude of the electroneurogram (ENG) has been shown to increase with increasing distance between the contacts when cuff electrodes are used to record peripheral nerve activity [9]. The effect is directly related to the propagation speed of the action potentials. Computer simulations have shown that the propagation velocity of action potentials in a length of a nerve axon can be decreased by subthreshold extracellular anodic currents. Slowing the action potentials is analogous to increasing the cuff length in that both result in longer intercontact delays, thus, larger signal outputs. This phenomenon is used to increase the amplitudes of whole nerve recordings obtained with a short cuff electrode. Computer simulations predicting the slowing effect of anodic currents as well as the experimental verification of this effect are presented. The increase in the amplitude of compound action potentials (CAP's) is demonstrated experimentally in an in vitro preparation. This method can be used to improve the signal-to-noise ratios when recording from short nerve segments where the cuff length is limited.

Closed-loop stimulation of hypoglossal nerve in a dog model of upper airway obstruction.

Electrical stimulation of upper airway (UAW) muscles has been under investigation as a treatment method for obstructive sleep apnea (OSA). Particular attention has been given to the electrical activation of the genioglossal muscle, either directly or via the stimulation of the hypoglossal nerve (HG), since the genioglossus is the main tongue protrusor muscle. Regardless of the stimulation site or method, an implantable electrical stimulation device for OSA patients will require a reliable method for detection of obstructive breaths to apply the stimulation when needed. In this paper, we test the hypothesis that the activity of the HG nerve can be used as a feedback signal for closed-loop stimulation of the HG nerve in an animal model of UAW obstruction where a force is applied on the submental region to physically narrow the airways. As an advantage, the method uses a single electrode for both recording and stimulation of the HG nerve. Simple linear filtering techniques were found to be adequate for producing the trigger signal for the electrical stimulation from the HG recordings. Esophageal pressure, which was used to estimate the size of the UAW passage, returned to the preloading values during closed-loop stimulation of the HG nerve. The data demonstrate the feasibility of the closed-loop stimulation of the HG nerve using its activity as the feedback signal.

Effects of induced electric fields on finite neuronal structures: a simulation study.

In this paper we present an analysis of magnetic stimulation of finite length neuronal structures using computer simulations. Models of finite neuronal structures in the presence of extrinsically applied electric fields indicate that excitation can be characterized by two driving functions: one due to field gradients and the other due to fields at the boundaries of neuronal structures. It is found that boundary field driving functions play an important role in governing excitation characteristics during magnetic stimulation. Simulations indicate that axons whose lengths are short compared to the spatial extent of the induced field are easier to excite than longer axons of the same diameter. Simulations also indicate that independent cellular dendritic processes are probably not excited during magnetic stimulation. Analysis of the temporal distribution of induced fields indicates that the temporal shape of the stimulus waveform modulates excitation thresholds and propagation of action potentials.