Response properties of the refractory auditory nerve fiber.

The refractory characteristics of auditory nerve fibers limit their ability to accurately encode temporal information. Therefore, they are relevant to the design of cochlear prostheses. It is also possible that the refractory property could be exploited by prosthetic devices to improve information transfer, as refractoriness may enhance the nerve's stochastic properties. Furthermore, refractory data are needed for the development of accurate computational models of auditory nerve fibers. We applied a two-pulse forward-masking paradigm to a feline model of the human auditory nerve to assess refractory properties of single fibers. Each fiber was driven to refractoriness by a single (masker) current pulse delivered intracochlearly. Properties of firing efficiency, latency, jitter, spike amplitude, and relative spread (a measure of dynamic range and stochasticity) were examined by exciting fibers with a second (probe) pulse and systematically varying the masker-probe interval (MPI). Responses to monophasic cathodic current pulses were analyzed. We estimated the mean absolute refractory period to be about 330 micros and the mean recovery time constant to be about 410 micros. A significant proportion of fibers (13 of 34) responded to the probe pulse with MPIs as short as 500 micros. Spike amplitude decreased with decreasing MPI, a finding relevant to the development of computational nerve-fiber models, interpretation of gross evoked potentials, and models of more central neural processing. A small mean decrement in spike jitter was noted at small MPI values. Some trends (such as spike latency-vs-MPI) varied across fibers, suggesting that sites of excitation varied across fibers. Relative spread was found to increase with decreasing MPI values, providing direct evidence that stochastic properties of fibers are altered under conditions of refractoriness.

Analysis of monophasic and biphasic electrical stimulation of nerve.

In an earlier study, biphasic and monphasic electrical stimulation of the auditory nerve was performed in cats with a cochlear implant. Single-unit recordings demonstrated that spikes resulting from monophasic and biphasic stimuli have different thresholds and latencies. Monophasic thresholds are lower and latencies are shorter under cathodic stimulation. Results from stochastic simulations of a biophysical model of electrical stimulation are similar. A simple analysis of a linear, "integrate to threshold" membrane model accounts for the threshold and latency differences observed experimentally and computationally. Since biphasic stimuli are used extensively in functional electrical stimulation, this analysis greatly simplifies the biophysical interpretation of responses to clinically relevant stimuli by relating them to the responses obtained with monophasic stimuli.

BDNF synthesis in spiral ganglion neurons is constitutive and CREB-dependent.

Brain-derived neurotrophic factor (BDNF), which supports spiral ganglion neuron (SGN) survival in vivo and in vitro, is synthesized by SGNs. The BDNF gene generates multiple different transcripts, each from its own promoter region. Using reverse transcriptase-polymerase chain reaction (RT-PCR), we find that SGNs express only the downstream transcripts III and IV in vivo and in vitro. Using RT-PCR assays of BDNF transcripts and transfection of BDNF promoter-reporter constructs, we tested the hypothesis, originally derived from studies of cortical neurons, that depolarization induces BDNF expression via a signaling pathway that includes Ca2+/calmodulin-dependent kinases (CaMKs) and the transcription factor, Ca2+/cyclic AMP response element binding protein (CREB). In contrast, we found that in SGNs in vivo BDNF expression is constitutive and is not increased by electrical activation. Similarly, BDNF expression in vitro is not increased by stimuli that activate CREB, including depolarization, cAMP, or transfection of activated CaMK mutants. However, transfection of dominant-negative CREB mutants did abrogate gene expression driven by BDNF promoters III and IV, indicating that CREB is necessary for constitutive BDNF expression. Thus, BDNF synthesis within SGNs makes possible an autocrine or paracrine mechanism that can contribute to support SGN survival but SGNs are distinctive in that this mechanism is constitutive and not activity-regulated.

The effects of interpulse interval on stochastic properties of electrical stimulation: models and measurements.

It is known that some cochlear implant users have improved speech perception using higher rates of interleaved pulsatile stimulation. There are, however, significant limitations on their performance presumably due in part to temporal and spatial interactions. To address these limitations, we have examined refractory characteristics of the auditory nerve using experimental animal models and computational simulations. A stochastic model of the node of Ranvier modified for mammalian sodium channel kinetics has been developed to calculate the masked input-output (I/O) functions for different interpulse intervals (IPI) [26]. The model is based upon 1000 voltage-gated sodium channels and incorporates parameters such as nodal resistance and capacitance. The relative spread (RS) [35] calculated from the I/O functions was typically 0.03 for 17 different IPIs between 450 micros and 6 ms for cathodal stimuli. For IPI = 830 and 870 micros, the RS was ten times greater than those for other IPIs. Although it is not fully understood how the electrically evoked compound action potential (EAP) data are related to single fiber data, the RS of single fibers is a partial contributor [19]. We have measured the EAP using a monopolar intracochlear stimulating electrode and a recording electrode placed directly on the nerve and have observed changes in slope of EAP growth functions consistent with the theoretical RS values. These results have significant implications for speech coding in a cochlear implant since they suggest an increased membrane noise for pulse trains of specific rates.

Auditory nerve responses to monophasic and biphasic electric stimuli.

Charge-balanced, biphasic stimulus pulses are commonly used in implantable cochlear prostheses as they can be safely delivered to living tissue. However, monophasic stimuli are more efficient (i.e. producing lower thresholds) and likely provide more spatially selective excitation of nerve fibers. We examined the neural responses to monophasic, 'pseudomonophasic', and biphasic stimuli to better understand the inherent tradeoffs of these stimuli. Using guinea pig and cat animal models, we compared the auditory nerve responses to both 40 micros monophasic and 40 micros/phase biphasic stimuli using both electrically evoked compound action potential and single-fiber recordings. We also made comparisons using a computational model of the feline auditory nerve fiber. In all cases, our stimuli were cathodic monophasic and cathodic-first biphasic pulses. As expected, monophasic stimuli provided lower thresholds relative to biphasic stimuli. They also evoked responses with relatively longer latencies. We also examined responses to charge-balanced biphasic pulses composed of two phases of differing duration (i.e. pseudomonophasic stimuli). The first phase was fixed at 40 micros, while the second phase was systematically varied from 40 to 4000 micros. With a relatively long second phase, we hypothesized that these stimuli would provide some of the beneficial features of monophasic stimuli. Both the gross-potential and single-fiber data confirmed this and indicate that the largest incremental effects of changing the second-phase duration occur for durations less than 500 micros. Consideration of single-fiber data and computer simulations suggest that these results are consistent with the neural membrane acting as a leaky integrator. The computer simulations also suggest that the integrative properties at least partially account for the difference between our monophasic-biphasic results and previously published data. Our results apply to cathodic-leading stimuli; due to differing patterns of membrane depolarization, they may not be applicable to situations using anodic-leading stimuli. Finally, we observed differences between the guinea pig and cat response patterns. Compared to cats, guinea pigs produced smaller monophasic vs. biphasic threshold differences. This interspecies disparity may be due to differences in cochlear anatomy.

A longitudinal study of electrode impedance, the electrically evoked compound action potential, and behavioral measures in nucleus 24 cochlear implant users.

OBJECTIVE: The primary goal of this study was to examine changes that may occur in electrode impedance, electrically evoked compound action potential (EAP) threshold and slope of the EAP growth function, and behavioral measures of threshold T-level) and maximum comfort (C-level) over time in both adult and child cochlear implant users. Secondary goals were to determine whether changes in these measures are consistent between children and adults, and to determine whether behavioral measures (MAP T- and C-levels) and electrophysiologic measures (EAP thresholds) exhibit the same trends over time. DESIGN: Thirty-five children and 33 adults implanted with the Nucleus CI24M between November 1996 and August 1999 participated in this study. Subjects were included in this study if 1) they had used their implant for at least 1 yr after device connection, and 2) they had participated in the necessary data collection at a minimum number of the time intervals assessed in this study. EAP threshold, slope of the EAP growth function, and common ground electrode impedance measures were collected intraoperatively, at initial stimulation, and at several subsequent visits up to 2 yr post initial stimulation. MAP T- an d C-levels weremeasured at initial stimulation and at the same time intervals as described above. RESULTS: Changes in electrode impedance, EAP thresholds, and slope of the EAP growth function from measures made intraoperatively, at initial stimulation, and at 1 to 2 mo post initial stimulation were similar in both children and adults. Beyond the 1- to 2-mo visit, children exhibited significant increases in electrode impedance, EAP thresholds, slope, and MAP T-levels, whereas these samemeasures in adults remained relatively stable. EAP thresholds in children stabilized by the 3- to 8-mo visit, and electrode impedance stabilized by the 6- to 8-mo visit, while slope of the EAP growth function, MAP T-levels,and MAP C-levels werestable by 1 yr post initial stimulation. C-levels in adults increased up to 1 yr post initial stimulation; however, the amount of increase was much smaller than that seen in children. In both children and adults, longitudinal trends in EAP thresholds mirrored T-level more closely than C-level. CONCLUSIONS: The results of this study suggest that peripheral changes occur in many children that do not generally occur in adults within the first year of cochlear implant use. One implication of these results is that if EAP thresholds are to be used to assist in programming the speech processor for children, it is best to make those measures at the same time interval as device programming rather than using measures made intraoperatively or at the initial programming session to set MAP levels at later visits.

The neuronal response to electrical constant-amplitude pulse train stimulation: evoked compound action potential recordings.

The purpose of this study was to gain a greater understanding of the electrically evoked compound action potential (EAP) responses to pulse train stimulation. Analysis of EAP amplitude responses suggested that an alternating pattern varied depending upon stimulus level, interpulse interval (IPI), stimulus waveform, and stimulus polarity. Stimulus level-dependent recovery was seen in the cat and the guinea pig: higher stimulus level tended to provide faster recovery. Both polarity-dependent recovery and polarity-dependent adaptation were observed in the cat and these stimulus polarity effects were less consistent in the guinea pig. The polarity-dependent recovery effect supports the hypothesis that anodal and cathodal stimuli excite different sites along auditory nerve fibers. Amplitude differences between the response to the second pulse and the steady-state response at the same IPI are significantly greater for anodal stimuli than for cathodal stimuli in all cats. These data suggest that there is a cumulative refractory effect in the auditory nerve of cats, especially in response to anodal stimuli.

The neuronal response to electrical constant-amplitude pulse train stimulation: additive Gaussian noise.

Experimental results from humans and animals show that electrically evoked compound action potential (EAP) responses to constant-amplitude pulse train stimulation can demonstrate an alternating pattern, due to the combined effects of highly synchronized responses to electrical stimulation and refractory effects (Wilson et al., 1994). One way to improve signal representation is to reduce the level of across-fiber synchrony and hence, the level of the amplitude alternation. To accomplish this goal, we have examined EAP responses in the presence of Gaussian noise added to the pulse train stimulus. Addition of Gaussian noise at a level approximately -30 dB relative to EAP threshold to the pulse trains decreased the amount of alternation, indicating that stochastic resonance may be induced in the auditory nerve. The use of some type of conditioning stimulus such as Gaussian noise may provide a more 'normal' neural response pattern.

An improved method of reducing stimulus artifact in the electrically evoked whole-nerve potential.

OBJECTIVE: Recording a compound action potential in response to electrical stimulation requires attention to minimize contamination due to electrical stimulus artifact. In patients implanted with the Nucleus 24 device, the electrically evoked whole-nerve potential (EAP) is recorded using a neural response telemetry (NRT) system. This system employs a forward-masking technique that greatly reduces stimulus artifact. However, theoretical considerations and experimental animal data suggest that the technique may distort the acquired EAP waveform under some situations. We proposed and evaluated a modification to the forward-masking technique that addresses this concern, particularly during collection of refractory recovery data. DESIGN: We first examined neural responses of the electrically stimulated auditory nerve using cat preparations. Through single-fiber recordings from cats, we demonstrated underlying physiological limitations likely encountered with the "standard" forward masking technique. We then recorded feline EAP waveforms using both the standard technique and our proposed, modified, technique. Finally, we collected EAP data from human cochlear implant patients using both artifact reduction methods. These comparisons allowed us to evaluate the effectiveness of our modification. RESULTS: The cat EAP data demonstrated that the standard forward-masking technique currently in use in the Nucleus NRT system can distort the EAP waveform when the nerve is partially refractory. In the cat, this distortion resulted in forward-masking recovery curves with artifactually prolonged recovery times and inaccurate latency trends. Similar effects were observed in the comparison of human recovery curves obtained using both the standard and modified techniques. In some cases, the modified technique produced EAP waveforms with more clearly defined peaks than were obtainable with the standard method. CONCLUSIONS: Consideration should be given to implementing our modified forward-masking artifact reduction scheme, because it introduces less distortion of the EAP waveform and accordingly provides for more accurate assessment of the refractory properties of the electrically stimulated nerve.

The relationship between EAP and EABR thresholds and levels used to program the nucleus 24 speech processor: data from adults.

OBJECTIVE: The objective of this study was to determine the relationship between electrically evoked whole nerve action potential (EAP) and electrical auditory brain stem response (EABR) thresholds and MAP threshold (T-level) and maximum comfort level (C-level) for subjects who use the Nucleus 24 cochlear implant system. DESIGN: Forty-four adult Nucleus 24 cochlear implant users participated in this study. EAP thresholds were recorded using the Neural Response Telemetry System developed by Cochlear Corporation. EABR thresholds were measured for a subset of 14 subjects using standard evoked potential techniques. These physiologic thresholds were collected on a set of five electrodes spaced across the cochlea, and were then compared with behavioral measures of T-level and C-level used to program the speech processor. RESULTS: EAP thresholds were correlated with MAP T- and C-levels; however, the correlation was not strong. A technique for improving the correlation by combining measures of T- and C-levels made on one electrode with the EAP thresholds was presented. Correlations between predicted and measured T- and C-levels using this technique were 0.83 and 0.77, respectively. Similar results were obtained using the EABR thresholds for a smaller set of subjects. In general, EABR thresholds were recorded at levels that were approximately 4.7 programming units lower than EAP thresholds. CONCLUSIONS: Either EAP or EABR thresholds can be used in combination with a limited amount of behavioral information to predict MAP T- and C-levels with reasonable accuracy.

Comparison of EAP thresholds with MAP levels in the nucleus 24 cochlear implant: data from children.

OBJECTIVE: The purpose of this study is to examine the relationship between the electrically evoked compound action potential (EAP) thresholds and the MAP thresholds (T-levels) and maximum comfort levels (C-levels) in children implanted with the Nucleus 24 device. DESIGN: EAP thresholds were measured using the Neural Response Telemetry system of the Nucleus 24 device. Twenty children implanted with the Nucleus 24 cochlear implant participated in this study. EAP thresholds were compared with the behavioral measures of T- and C-level used to construct the MAP these children used on a daily basis. For these subjects, both EAP and MAP T- and C-levels were obtained the same visit, which occurred at 3 to 5 mo postconnection. RESULTS: EAP thresholds were shown to fall between MAP T- and C-level for 18 of 20 subjects tested; however, considerable variability across subjects was noted. On average, EAP thresholds fell at 53% of the MAP dynamic range. Correlations between EAP threshold and MAP T- and C-level improved substantially when combined with behavioral measures obtained from one electrode in the array. CONCLUSIONS: Moderate correlations were found between EAP thresholds and MAP T- and C-levels for the children participating in this study. However, a technique is described for improving the accuracy of predictions of MAP T- and C-levels based on EAP data combined with a small amount of behavioral information.

Electrically evoked compound action potentials recorded from subjects who use the nucleus CI24M device.

The ability to directly measure the response to a pulse with the NRT opens the possibility of using this system to characterize the responses to more complex stimuli. An example is the responses to constant-amplitude pulse trains. With further changes in the software that controls the implant, it may be possible to characterize the responses to modulated pulse trains or other stimuli that better approximate the type of stimuli that are normally used with a cochlear implant speech processor.

An empirically based model of the electrically evoked compound action potential.

The relationship between electrically evoked single-fiber action potentials and the electrically evoked compound action potential of the auditory nerve is of interest to those attempting to model such responses with computational techniques. It also relates to efforts to exploit the gross potentials that can now be recorded by some implantable cochlear prostheses. In this paper, we develop a computational model of the auditory nerve response to single, pulsatile, electrical stimuli based upon the response characteristics obtained from 230 single fibers of 13 cats. These fibers were stimulated by brief (39s) monophasic cathodic stimuli delivered by a monopolar intracochlear electrode. The data were pooled to obtain an estimate of the distribution of fiber thresholds. Post-stimulus time histograms were modeled using Poisson functions and adjusted to account for empirically determined latency and jitter characteristics. The probabilistic nature of single-fiber input-output functions (i.e. Verveen's (1961) 'relative spread') was also modelled. PST histograms from 5000 modelled fibers were then summed and convolved with an estimated 'unit potential' following the method of Goldstein and Kiang (1958). This convolution produced modelled compound action potentials, which were then compared with experimentally obtained data. Manipulations of model parameters affecting threshold, jitter, and relative spread suggest that the most important determinant of the shape of the EAP amplitude-level function is the threshold distribution. A model based solely on threshold distribution produces an EAP input-output function similar to one that accounts for probabilistic single-fiber input-output functions. Discrepancies between these two models do occur if the threshold distribution function is compressed significantly, as might be the case in pathological cochleae with altered distributions or numbers of nerve fibers.

Electrically evoked single-fiber action potentials from cat: responses to monopolar, monophasic stimulation.

We recorded action potentials from single auditory-nerve fibers of cats using monophasic current pulses delivered by a monopolar intracochlear electrode. These simple stimuli provided a means of investigating basic properties and hypotheses of electrical excitation. Standard micropipette recording techniques were used. Responses to anodic (positive) and cathodic (negative) stimulus pulses were recorded separately to evaluate stimulus polarity effects. Mean spike (action potential) latency was polarity dependent, with greater latencies for cathodic stimulation. Threshold stimulus level was also polarity dependent, with relatively lower cathodic thresholds. Both effects are consistent with trends reported in the compound action potential. Variability in single-fiber latency (i.e., jitter) was dependent upon stimulus polarity. In contrast, the slope of single-fiber input-output functions failed to show a clear polarity dependence, although such trends have been seen in the compound action potential data. We also observed a relatively greater degree of adaptation over time with anodic stimulation. Bimodal post-stimulus-time histograms were recorded in a small number (2%) of fibers, supporting the hypothesis that both the peripheral (dendritic) and central axonal processes are excitable with the same stimulus polarity, in a limited number of cases. This observation, together with analyses of interactions among measures of latency, threshold, and jitter, is consistent with the hypothesis that, with monopolar intracochlear stimulation, most fibers are stimulated at axonal (modiolar) sites and a minority of fibers nearest the electrode are stimulable at their peripheral processes.

Relationship between EABR thresholds and levels used to program the CLARION speech processor.

The purpose of this study was 1) to describe the relationship between electrically evoked auditory brain stem response (EABR) thresholds and the behavioral measures needed to program the speech processor of the CLARION Multi-Strategy Cochlear Implant, and 2) to determine whether the relationship between EABR threshold and the behavioral levels used to program the Clarion device was correlated with the temporal integration abilities of these subjects. The EABR thresholds, psychophysical thresholds, and the Clarion speech processor programming levels were recorded from 29 postlingually deafened adults. The mean EABR thresholds approximated most comfortable levels (M levels) for the programming stimulus. However, intrasubject variability was substantial. Significant intrasubject variability in temporal integration also was observed. Correlations were found between the ability of a cochlear implant user to perform temporal integration and the relationship between his or her EABR threshold and the threshold for the programming stimulus.

Summary of results using the nucleus CI24M implant to record the electrically evoked compound action potential.

OBJECTIVE: This study outlines a series of experiments using the neural response telemetry (NRT) system of the Nucleus CI24M cochlear implant to measure the electrically evoked compound action potential (EAP). The goal of this investigation was to develop a protocol that allows successful recording of the EAP in a majority of CI24M cochlear implant users. DESIGN: Twenty-six postlingually deafened adults participated in this study. A series of experiments were conducted that allowed us to examine how manipulation of stimulation and recording parameters may affect the morphology of the EAP recorded using the Nucleus NRT system. RESULTS: Results of this study show consistent responses on at least some electrodes from all subjects. Cross-subject and cross electrode variations in both the growth of the response and the temporal refractory properties of the response were observed. The range of stimulus and recording parameters that can be used to record the EAP with the Nucleus NRT system is described. CONCLUSIONS: Using the protocol outlined in this study, it is possible to reliably record EAP responses from most subjects and for most electrodes in Nucleus CI24M cochlear implant users. These responses are robust and recording these responses does not require that the subject sleep or remain still. Based on these results, a specific protocol is proposed for measurement of the EAP using the NRT system of the CI24M cochlear implant. Potential clinical implications of these results are discussed.

Pseudospontaneous activity: stochastic independence of auditory nerve fibers with electrical stimulation.

We describe a novel signal processing strategy for cochlear implants designed to emphasize stochastic independence across the excited neural population. The strategy is based on the observation that high rate pulse trains may produce random spike patterns in auditory nerve fibers that are statistically similar to those produced by spontaneous activity in the normal cochlea. We call this activity 'pseudospontaneous'. A supercomputer-based computational model of a population of auditory nerve fibers suggests that different average rates of pseudospontaneous activity can be created by varying the stimulus current of a fixed-amplitude, high-rate pulse train, e.g. 5000 pps. Electrically-evoked compound action potentials recorded in a human cochlear implant subject are consistent with the hypothesis that such a stimulus can desynchronize the fiber population. This desynchronization may enhance neural representation of temporal detail and dynamic range with a cochlear implant and eliminate a major difference between acoustic and electric hearing.

Electrically evoked compound action potentials of guinea pig and cat: responses to monopolar, monophasic stimulation.

We recorded electrically evoked compound action potentials (EAPs) from guinea pigs and cats using monophasic current pulses delivered by a monopolar intracochlear electrode. By using simple stimuli, we sought results that could shed light on basic excitation properties of the auditory nerve. In these acute experiments, the recording electrode was placed directly on the auditory nerve. Responses to anodic and cathodic stimulus pulses were recorded separately to evaluate stimulus polarity effects. Several polarity-dependent properties were observed. Both EAP morphology and latency were polarity-dependent, with greater latencies for cathodic stimulation. Threshold stimulus level was also polarity-dependent, but in different directions in the two species: cats had lower cathodic thresholds while guinea pigs had lower anodic thresholds. We also observed that the slopes of the EAP amplitude-level functions depended upon stimulus polarity. In most cases where EAP saturation amplitude could be measured, that amplitude was similar for anodic and cathodic stimuli, suggesting that either stimulus polarity can recruit all fibers, or at least a comparable numbers of fibers. The common findings (e.g., EAP morphology and polarity-dependent latency) observed in these two species suggest results that can be extrapolated to responses obtained in humans, while the species-specific findings (e.g., dependence of threshold on polarity) may point to underlying anatomical differences that caution against overgeneralization across species. Some of our observations also bear upon hypotheses of how electrical stimuli may excite different sites on auditory nerve fibers.

Preliminary experience with neural response telemetry in the nucleus CI24M cochlear implant.

OBJECTIVE: This study aimed to compare recordings of the electrically evoked whole nerve action potential (EAP) made using the reverse telemetry system of the Nucleus CI24M device with those recorded from individuals who use the Ineraid cochlear implant system. STUDY DESIGN: Data were collected in a prospective fashion from Nucleus CI24M cochlear implant users and compared with retrospective data collected from patients who use the Ineraid device. SETTING: All data were collected at the Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics. PATIENTS: Data are reported from 8 patients who use the Nucleus CI24M cochlear implant and 20 patients who use the Ineraid cochlear implant system. INTERVENTIONS: The interventions described in this study were diagnostic in nature. MAIN OUTCOME MEASURES: EAP growth and refractory recovery data are reported. EAP thresholds recorded from patients who use the Nucleus CI24M device also are compared with behavioral thresholds for the stimulus used to evoke the EAP as well as the stimulation levels needed to program the speech processor. RESULTS: EAP morphology, growth, and refractory recovery functions recorded using the Nucleus CI24M reverse telemetry system compared favorably with similar measures recorded from Ineraid cochlear implant users. CONCLUSIONS: Reasonable EAP responses can be recorded using the Nucleus CI24M device. More data are needed to determine whether the information about neural responsiveness available with this device will be clinically useful.