First, Ballestro et al. In contrast, eABR is a gross measure of neural activity, reflecting synchronous activity of those fibers most sensitive to low-level stimuli. Thus, there are several processing steps that have to be taken to go from what is being presented at the intracochlear electrode to what the SGN actually receives. Those steps include impedance in the electrode, fluid and bone, electrode position relative to the peripheral processes, site of excitation, extent of myelination, spread of excitation, temporal and spatial integration, etc.
Second, in contrast to our study, Ballestro et al. Third, Ballestro et al. Their hypothesis was that the foot amplitude of a given amplitude drives SGNs to subthreshold and that the steepness of the ramp then is used to control the evoked firing rate.
Fourth, Ballestro et al. That said, clinical presentation rates are higher e. Also, the fact that rampUP had lower thresholds than rampDOWN supports the hypothesis that a rising slope is important for efficient stimulation. For example, Yip et al. This waveform therefore likely takes advantages of the fact that animals are most sensitive to the cathodic phase 2 , 41 and that the action potential therefore is triggered during this phase.
In contrast, the rectangular anodic shape does not likely contribute to the firing, but rather ensures charge-balance. Yip et al. In general, our fidings are in line with the literature. We found a lower threshold with ramped pulses than with rectangular pulses, and we found that a rising ramp is beneficial.
That said, it is important to stress that the ramped current slope used in this study was not perfect, but stepwise, due to hardware limitations. Most studies with human CI users and with animals have demonstrated a good correlation between eABR and psychophysical thresholds 42 , 43 , 44 , 45 , although there is a large variability across and within subjects, and with different methodological approaches. We would therefore also expect lower psychophysical threshold with ramped pulses in mice, as observed in our eABR data.
In this study, the steeper growth of wave II with ramped pulses that we observed suggests that maximum stimulation most comfortable level can be obtained with less charge. Yet, it would only be beneficial if the number of discriminable loudness level steps are, at least, maintained. In our eABR recordings, the upper limit of electric stimulation was in most mice determined by the presence of a facial nerve response and the numbers of intensity steps is unknown.
The potential of a reduced dynamic range and thus reduced power consumption needs to be further investigated with psychophysical data. This indicates that the direction rising or declining of the stimulus ramp matters. As mentioned, a steeper growth function implies a higher recruitment rate of neurons with increasing intensity. Various mechanisms have been found to contribute to slope steepness. First, activation of auditory nerve fibers is known to depend on the electrode configuration, as demonstrated by greater eABR growth with monopolar stimulation than with bipolar stimulation 19 , 34 , One suggested explanation for this is that there are different sites of excitation along the SGN.
A more confined bipolar stimulation fields is proposed to activate sites on the peripheral processes, while monopolar stimulation activates more central sites on the SGN Thus, activation of more densely placed SGNs at the modulus might account for the steeper growth function observed with monopolar stimulation as stimulus level increases The site-of-excitation is also influenced by level.
In particular, bipolar activation is proposed to switch from a peripheral to a more central site on auditory nerve fibers. This switch is supported by eABR latency data that show that latencies are shorter with monopolar than with bipolar stimulation Second, Shepherd et al. These data were supported by Frijns et al. Their model also predicted a lower threshold and higher spatial selectivity with electrodes in the dendritic position 30 , Based on this, one could speculate that ramped pulses excite sites on the auditory nerve fiber distinct from rectangular pulses to produce steeper growth function.
Interestingly, immunostainings show that Kv. Indeed, it would be interesting to explore how and at which site ramped and rectangular pulses excite the auditory nerve fibers, using latency data from single- or multiunit neuronal recordings. Also, if ramped stimuli activate KLT channels, which promotes a sharply timed action potential 48 , then we would expect there to be less temporal jitter in the firing of single neurons close to the stimulated electrode.
Third, a faster recruitment of more neurons and thus a steeper slope could also be explained by a larger current spread, which goes against the hypothesis that ramped pulses create a more focused stimulation. Spread of excitation with ramped pulses is not addressed in the study, but is an appealing topic of future research.
It is known that both the anodic and cathodic phase in a rectangular pulse can elicit neural responses 2 , 25 , In human CI listeners, studies have shown that at supra-thresholds, the anodic phase is more efficient than the cathodic phase 25 , 27 , In contrast, animals show greater sensitivity to the cathodic phase 2 , The reason for this discrepancy is yet to be clarified but computational models suggest two possible explanations 30 , Second, that at high levels of cathodic stimulation, the propagation of the spike is blocked by a strong hyperpolarization at more central sites of the fiber, which eventually leads to higher levels needed with cathodic pulses than anodic pulses.
In the present study, we found that cathodic-first biphasic pulses were 1. The result supports previous animal, not human, studies and is likely related to the relatively healthy peripheral processes in our acutely deafned mice. This is an important point in terms of clinical translation. Carlyon et al. We therefore hypothesized that such a model could predict the lower thresholds we observed with ramped pulses and could be used as a simple tool to understand how the waveform being integrated by SGNs actually looks.
Details of our model can be found in Methods and in Carlyon et al. In short, it passes pulse shapes through a simple lowpass filter. The predicted threshold then corresponds to a fixed RMS level at the filter output. We implemented this model by using the animal filter as an attempt to explain the eABR threshold that we observed, without taking the slope-sensitivity into account thus, without modelling KLT channel dynamics; see e. It is important to note that our model does not take polarity effects into consideration.
Interestingly, the filtered output of rampUP and Rec looked similar for the three phase durations Fig. Our model predicted lower charge thresholds for all three ramped pulses compared to Rec Fig. In contrast, our model did not capture the observed higher threshold we observed with rampDOWN. With respect to phase duration, our model predicted that the amount of charge would be constant as a function of phase duration Fig.
Nonetheless, less charge was needed with rampUP compared to Rec for longer phase durations Fig. The results show the limitations of the model. First, that the model is calibrated to a reference point in the animal data see Methods. Second, that the cut-off frequencies in the filter model, which are based on behavioural thresholds in cats, might not fit physiological thresholds.
This suggests that the time course over which electrical charge is recovered is different for physiological and behavioural thresholds. Third, that the model is not adapted to mice. For instance, Carlyon et al. One could therefore speculate that there also would be species differences relevant for integration of charge between cats and mice, which is not implemented in the model.
The model could, however, capture the difference in threshold between rectangular and ramped pulses observed in the mouse in terms of current level amplitude Fig. Comparison of measured wave II thresholds and predicted thresholds from the lowpass filter model. Note the input level has an arbitrary unit. Only cathodic-first polarity is shown.
Overall, this simple lowpass model could show differences in thresholds between ramped and rectangular pulses with a short interpulse gap without taking the slope-sensitivity into account. The present study was performed in mice. To put the results into a clinical perspective, we will highlight four major differences between mice and humans.
First, mice use a higher frequency range of hearing than humans do. Stimulating the most apical electrode target relatively mid-high frequencies, around 30 kHz However, it seems reasonable to expect similar benefits of ramped pulses also at lower frequencies. Second, other key differences between mice and humans are the length of the peripheral processes and the degree of myelination of the soma.
Third, the scala tympani is smaller in mice than it is in humans, which makes it possible to position the electrode closer to the neuronal processes and thereby stimulate the auditory nerve more efficiently in the mouse, as found in a study in cats This might produce a larger spread of excitation from one electrode in mice and possibly underestimate the potential beneficial effect that ramped pulses might have on spatial selectivity.
Finally, the small head size of mice is likely to contribute to a more sensitive eABR measure compared to those obtained in humans. The differences between ramped and rectangular pulse shapes observed in mice may therefore be larger in humans. Nonetheless, the data presented in our study show that it is possible to use ramped pulse shapes for CI stimulation but more work is needed to investigate their clinical relevance.
Taken together, our results show that rampUP pulses at the level of the brainstem have a higher charge-efficiency. This provides useful insights into the general understanding of the electrode-neuron interface. All animal procedures were approved by the Veterinary Office of the Canton of Basel, Switzerland and complied with guidelines established by the Basel University, Switzerland.
The left ear was used as the experimental ear. Details of the surgical approach and electrode array are provided in Navntoft et al. Local analgesic 0. Body temperature was maintained at A post-auricular incision was made and the sternocleidomastoid muscle was retracted to reveal the tympanic bulla periosteum. The bulla was then opened and further extended dorsally to visualize the round window niche.
Animals were deafened to eliminate electrophonic responses. The lead wire was then coiled inside the bulla and the incision was closed. A silver wire ground ball was placed in a subcutaneous pocket in the neck. The impedance of each electrode was measured before and after the recording session to ensure that all electrodes were functioning.
The stimulation current was for all animals always below the compliance limit of respective electrode contact. Four pulse shapes and two polarities giving eight waveforms were tested Fig. The rectangular pulse shape Rec has, as its name indicates, a rectangular shape with a flat phase amplitude. The three ramped shapes are defined according to their slope, specifically the rate at which the injected current increases or decreases linearly over time.
In rampUP, for both the first and the second phase, the slope ramped from zero at the phase onset to a specified amplitude current level at the phase offset. In rampDOWN, for both the first and the second phases, the slope ramped from a specified amplitude current level at the phase onset to zero at the phase offset. In rampLONG, for the first phase, the slope ramped from a specified amplitude current level at the phase onset to zero at the phase offset.
For the second phase, the slope ramped from zero at the phase onset to a specified amplitude current level at the phase offset. Both anodic- and cathodic-first polarities were tested. Charge per phase for rectangular pulses was calculated as pulse width times current level amplitude, and for ramped pulses it was calculated as pulse width times current level amplitude divided by two.
ABR recordings were performed in soundproof and electrically-shielded booth under anesthesia as detailed above. Click trains reps: 0. ABR were recorded by using stainless steel electrodes positioned at the vertex, hind leg, and behind the pinna of the ipsilateral ear active, ground and reference, respectively.
To obtain a higher sampling resolution of the eABR response, we used an up-sampling technique. Four hundred repetitions were presented at each stimulus level and delivered at a rate of Both anodic- and cathodic-first pulses were tested, with anodic-first having an anodic phase followed by a cathodic phase and with cathodic-first having a cathodic phase followed by an anodic phase.
The conditions were presented in randomized order. Stimulation artefacts are shown in Supplementary Fig. The stimulus artefact in eABR was removed by using linear interpolation before the signal was bandpass filtered in a way similar to that for aABR Supplementary Fig. Epochs were then extracted, baseline corrected and averaged.
In order to cancel the stimulation artefact from traces with an interpulse gap of 2. Amplitude was defined as the voltage difference between the positive peak and the following trough. Latency was defined as timing of the peak. Threshold was determined as the lowest charge level needed to evoke a wave amplitude above 0. To ensure that no remaining stimulus artefact was present at wave II, an alternating polarity artefact reduction was performed.
The data for each pulse shape was averaged over both polarities to cancel out the polarity-symmetric stimulus artefact. We verified that the thresholds and growth function of the averaged data were between the thresholds and growth function for the single polarities, respectively Supplementary Fig. That said, we cannot exclude a potential remaining fully-decayed stimulus artefact at higher stimulation levels. However, this should not affect the threshold value and the slope analysis. Thus, the slope of line 2 was forced to be 0 or negative to get the saturation point of the growth function.
Our filter model is based on the model developed by Carlyon et al. In brief, our model assumes that the electric waveform is passed through a lowpass filter and that the threshold corresponds to a fixed RMS level of the filter output. The windows spanned one period of the stimulus. That period was the same as the one used in the eABR recordings giving a presentation rate of Finally, thresholds were assumed to be inversely proportional to the maximum of the RMS output on any window.
The output was reported in dB re an arbitrary unit. To analyse and compare the overall effects of amplitudes and latencies of responses, factor analyses were performed by using a mixed model with random effects in the statistical software program called JMP version Normality and homogeneity were checked by visual inspecting plots of residuals against fitted values.
The pulse shape, polarity and pulse duration were fixed factors, while mouse was set as a random factor. A paired t-test was used to test the aABR threshold before and after neomycin. Correlations between aABR and eABR thresholds and growth function slopes were tested for with a Pearson correlation and a two-tailed p-value. Friesen, L. Speech recognition in noise as a function of the number of spectral channels: Comparison of acoustic hearing and cochlear implants.
Miller, C. Electrically evoked single-fiber action potentials from cat: Responses to monopolar, monophasic stimulation. Rubinstein, J. Analysis of monophasic and biphasic electrical stimulation of nerve. IEEE Trans. Ballestero, J. Reducing current spread by use of a novel Pulse shape for electrical stimulation of the auditory nerve. Trends Hear.
Google Scholar. Yip, M. Energy-efficient waveform for electrical stimulation of the cochlear nerve. Recugnat, M. Abstract: Modelling electrically evoked compound action potential of single neuron responses to predict polarity and pulse shape effects on spiral ganglion neurons under electro-stimulation.
In Conference on Implantable Auditory Prostheses Smith, K. Phosphoinositide modulation of heteromeric Kv1 channels adjusts output of spiral ganglion neurons from hearing mice. Mo, Z. Negm, M. Boulet, J. Predictions of the vontribution of HCN half-maximal activation potential heterogeneity to variability in intrinsic adaptation of spiral ganglion neurons. Ferragamo, M. Octopus cells of the mammalian ventral cochlear nucleus sense the rate of depolarization.
Joshi, S. Poster: Low-threshold potassium channels and their effect on polarity sensitivity of the electrically stimulated auditory nerve. CIAP Meet. Dorman, M. Speech intelligibility as a function of the number of channels of stimulation for normal-hearing listeners and patients with cochlear implants. Fu, Q. Noise susceptibility of cochlear implant users: The role of spectral resolution and smearing.
Schvartz-Leyzac, K. Effects of electrode deactivation on speech recognition in multichannel cochlear implant recipients. Cochlear Implants Int. Croghan, N. Re-examining the relationship between number of cochlear implant channels and maximal speech intelligibility. Lotfi Navaii, M. Waveform efficiency analysis of auditory nerve fiber stimulation for cochlear implants.
Claussen, A. A mouse model of cochlear implantation with chronic electric stimulation. PLoS One 14 , 1—23 Shepherd, R. Electrical stimulation of the auditory nerve: The effect of electrode position on neural excitation. Miller, A. Across-species comparisons of psychophysical detection thresholds for electrical stimulation of the cochlea: II. Strength-duration functions for single, biphasic pulses.
Carlyon, R. Effect of inter-phase gap on the sensitivity of cochlear implant users to electrical stimulation. Electrical stimulation of the auditory nerve: II. Effect of stimulus waveshape on single fibre response properties. A model of electrically stimulated auditory nerve fiber responses with peripheral and central sites of spike generation.
Bahmer, A. The underlying mechanism of preventing facial nerve stimulation by triphasic pulse stimulation in cochlear implant users assessed with objective measure. Undurraga, J. The polarity sensitivity of the electrically stimulated human auditory nerve measured at the level of the brainstem. Spread of excitation varies for different electrical pulse shapes and stimulation modes in cochlear implants.
Macherey, O. Higher sensitivity of human auditory nerve fibers to positive electrical currents. Spitzer, E. Effect of stimulus polarity on physiological spread of excitation in cochlear implants. Intracochlear and extracochlear ECAPs suggest antidromic action potentials. Frijns, J. Spatial selectivity in a rotationally symmetric model of the electrically stimulated cochlea.
Ranck, J. Which elements are excited in electric stimulation of mammalian central nervous system: a review. Brain Res. Effect of pulse polarity on thresholds and on non-monotonic loudness growth in cochlear implant users. Electrical stimulation of the auditory nerve: Single neuron strength-duration functions in deafened animals. Functional responses from guinea pigs with cochlear implants. Electrophysiological and psychophysical measures.
Ramekers, D. Auditory-nerve responses to varied inter-phase gap and phase duration of the electric pulse stimulus as predictors for neuronal degeneration. Prado-Guitierrez, P. Effect of interphase gap and pulse duration on electrically evoked potentials is correlated with auditory nerve survival. Chatterjee, M. Sensitivity to pulse phase duration in cochlear implant listeners: Effects of stimulation mode.
Shannon, R. Threshold and loudness functions for pulsatile stimulation of cochlear implants. Polarity effects on neural responses of the electrically stimulated auditory nerve at different cochlear sites. Wieringen, A. Effects of waveform shape on human sensitivity to electrical stimulation of the inner ear. Asymmetric pulses in cochlear implants: Effects of pulse shape, polarity, and rate.
Abbas, P. Electrically evoked auditory brainstem response: Growth of response with current level. King, J. A physiological and behavioral system for hearing restoration with cochlear implants. Functional responses from guinea pigs with cochlear implants II. Changes in electrophysiological and psychophysical measures over time. Smith, D. Behavioral auditory thresholds for sinusoidal electrical stimuli in the cat. Single fiber mapping of spatial excitation patterns in the electrically stimulated auditory nerve.
Potential distributions and neural excitation patterns in a rotationally symmetric model of the electrically stimulated cochlea. McGinley, M. Rate thresholds determine the precision of temporal integration in principal cells of the ventral cochlear nucleus. Klop, W. A new method for dealing with the stimulus artefact in electrically evoked compound action potential measurements. Every pet parent needs this simple insturctional guide when adopting or shown by there vet.
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