Assessing Neural Synchrony in the Cochlear Nerve to Electrical Stimulation in Children With Auditory Neuropathy Spectrum Disorder.

OBJECTIVES: This study reported phase locking values (PLVs) that quantified the trial-to-trial phase coherence of electrically evoked compound action potentials in children with auditory neuropathy spectrum disorders (ANSD) and children with Gap Junction Beta 2 (GJB2) mutations, a patient population without noticeable cochlear nerve damage. DESIGN: PLVs were measured at three electrode locations in 11 children with ANSD and 11 children with GJB2 mutations. Smaller PLVs indicated poorer neural synchrony. A linear mixed-effects model was used to compare PLVs measured at different electrode locations between participant groups. RESULTS: After controlling for the stimulation level effect, children with ANSD had smaller PLVs than children with GJB2 mutations at all three electrode locations. CONCLUSIONS: Cochlear-implanted children with ANSD show poorer peripheral neural synchrony than children with GJB2 mutations.

Peripheral Neural Synchrony in Postlingually Deafened Adult Cochlear Implant Users.

OBJECTIVES: This paper reports a noninvasive method for quantifying neural synchrony in the cochlear nerve (i.e., peripheral neural synchrony) in cochlear implant (CI) users, which allows for evaluating this physiological phenomenon in human CI users for the first time in the literature. In addition, this study assessed how peripheral neural synchrony was correlated with temporal resolution acuity and speech perception outcomes measured in quiet and in noise in postlingually deafened adult CI users. It tested the hypothesis that peripheral neural synchrony was an important factor for temporal resolution acuity and speech perception outcomes in noise in postlingually deafened adult CI users. DESIGN: Study participants included 24 postlingually deafened adult CI users with a Cochlear™ Nucleus® device. Three study participants were implanted bilaterally, and each ear was tested separately. For each of the 27 implanted ears tested in this study, 400 sweeps of the electrically evoked compound action potential (eCAP) were measured at four electrode locations across the electrode array. Peripheral neural synchrony was quantified at each electrode location using the phase-locking value (PLV), which is a measure of trial-by-trial phase coherence among eCAP sweeps/trials. Temporal resolution acuity was evaluated by measuring the within-channel gap detection threshold (GDT) using a three-alternative, forced-choice procedure in a subgroup of 20 participants (23 implanted ears). For each ear tested in these participants, GDTs were measured at two electrode locations with a large difference in PLVs. For 26 implanted ears tested in 23 participants, speech perception performance was evaluated using consonant-nucleus-consonant (CNC) word lists presented in quiet and in noise at signal to noise ratios (SNRs) of +10 and +5 dB. Linear Mixed effect Models were used to evaluate the effect of electrode location on the PLV and the effect of the PLV on GDT after controlling for the stimulation level effects. Pearson product-moment correlation tests were used to assess the correlations between PLVs, CNC word scores measured in different conditions, and the degree of noise effect on CNC word scores. RESULTS: There was a significant effect of electrode location on the PLV after controlling for the effect of stimulation level. There was a significant effect of the PLV on GDT after controlling for the effects of stimulation level, where higher PLVs (greater synchrony) led to lower GDTs (better temporal resolution acuity). PLVs were not significantly correlated with CNC word scores measured in any listening condition or the effect of competing background noise presented at an SNR of +10 dB on CNC word scores. In contrast, there was a significant negative correlation between the PLV and the degree of noise effect on CNC word scores for a competing background noise presented at an SNR of +5 dB, where higher PLVs (greater synchrony) correlated with smaller noise effects on CNC word scores. CONCLUSIONS: This newly developed method can be used to assess peripheral neural synchrony in CI users, a physiological phenomenon that has not been systematically evaluated in electrical hearing. Poorer peripheral neural synchrony leads to lower temporal resolution acuity and is correlated with a larger detrimental effect of competing background noise presented at an SNR of 5 dB on speech perception performance in postlingually deafened adult CI users.

Relationships Between the Auditory Nerve's Ability to Recover From Neural Adaptation, Cortical Encoding of and Perceptual Sensitivity to Within-channel Temporal Gaps in Postlingually Deafened Adult Cochlear Implant Users.

OBJECTIVE: As a step toward identifying the origin of the across-electrode variation in within-channel gap detection thresholds (GDTs) measured in individual cochlear implant (CI) users, this study assessed the relationships between the auditory nerve's (AN's) ability to recover from neural adaptation, cortical encoding of and perceptual sensitivity to within-channel temporal gaps in postlingually deafened adult CI users. DESIGN: Study participants included 11 postlingually deafened adults with Cochlear Nucleus devices, including three bilaterally implanted participants. In each of the 14 ears tested, recovery from neural adaptation of the AN was measured using electrophysiological measures of the electrically evoked compound action potential at up to four electrode locations. The two CI electrodes in each ear showing the largest difference in the speed of adaptation recovery were selected for assessing within-channel temporal GDT. GDTs were measured using both psychophysical and electrophysiological procedures. Psychophysical GDTs were evaluated using a three-alternative, forced-choice procedure, targeting 79.4% correct on the psychometric function. Electrophysiological GDTs were measured using the electrically evoked auditory event-related potential (eERP) evoked by temporal gaps embedded in electrical pulse trains (i.e., the gap-eERP). Objective GDT was defined as the shortest temporal gap that could evoke a gap-eERP. Related-samples Wilcoxon Signed Rank test was used to compare psychophysical GDTs and objective GDTs measured at all CI electrode locations. It was also used to compare psychophysical GDTs and objective GDTs measured at the two CI electrode locations with different speeds or amounts of adaptation recovery of the AN. A Kendall Rank correlation test was used to assess the correlation between GDTs measured at the same CI electrode location using psychophysical or electrophysiological procedures. RESULTS: Objective GDTs were significantly larger than those measured using psychophysical procedures. There was a significant correlation between objective and psychophysical GDTs. GDTs could not be predicted based on the amount or the speed of adaptation recovery of the AN. CONCLUSIONS: Electrophysiological measures of the eERP evoked by temporal gaps can potentially be used to assess within-channel GDT in CI users who cannot provide reliable behavioral responses. The difference in adaptation recovery of the AN is not the primary factor accounting for the across-electrode variation in GDT in individual CI users.

The Relationship Between Cochlear Implant Speech Perception Outcomes and Electrophysiological Measures of the Electrically Evoked Compound Action Potential.

OBJECTIVE: This study assessed the relationship between electrophysiological measures of the electrically evoked compound action potential (eCAP) and speech perception scores measured in quiet and in noise in postlingually deafened adult cochlear implant (CI) users. It tested the hypothesis that how well the auditory nerve (AN) responds to electrical stimulation is important for speech perception with a CI in challenging listening conditions. DESIGN: Study participants included 24 postlingually deafened adult CI users. All participants used Cochlear Nucleus CIs in their test ears. In each participant, eCAPs were measured at multiple electrode locations in response to single-pulse, paired-pulse, and pulse-train stimuli. Independent variables included six metrics calculated from the eCAP recordings: the electrode-neuron interface (ENI) index, the neural adaptation (NA) ratio, NA speed, the adaptation recovery (AR) ratio, AR speed, and the amplitude modulation (AM) ratio. The ENI index quantified the effectiveness of the CI electrodes in stimulating the targeted AN fibers. The NA ratio indicated the amount of NA at the AN caused by a train of constant-amplitude pulses. NA speed was defined as the speed/rate of NA. The AR ratio estimated the amount of recovery from NA at a fixed time point after the cessation of pulse-train stimulation. AR speed referred to the speed of recovery from NA caused by previous pulse-train stimulation. The AM ratio provided a measure of AN sensitivity to AM cues. Participants' speech perception scores were measured using Consonant-Nucleus-Consonant (CNC) word lists and AzBio sentences presented in quiet, as well as in noise at signal-to-noise ratios (SNRs) of +10 and +5 dB. Predictive models were created for each speech measure to identify eCAP metrics with meaningful predictive power. RESULTS: The ENI index and AR speed individually explained at least 10% of the variance in most of the speech perception scores measured in this study, while the NA ratio, NA speed, the AR ratio, and the AM ratio did not. The ENI index was identified as the only eCAP metric that had unique predictive power for each of the speech test results. The amount of variance in speech perception scores (both CNC words and AzBio sentences) explained by the eCAP metrics increased with increased difficulty under the listening condition. Over half of the variance in speech perception scores measured in +5 dB SNR noise (both CNC words and AzBio sentences) was explained by a model with only three eCAP metrics: the ENI index, NA speed, and AR speed. CONCLUSIONS: Of the six electrophysiological measures assessed in this study, the ENI index is the most informative predictor for speech perception performance in CI users. In agreement with the tested hypothesis, the response characteristics of the AN to electrical stimulation are more important for speech perception with a CI in noise than they are in quiet.

Relationships Between the Auditory Nerve Sensitivity to Amplitude Modulation, Perceptual Amplitude Modulation Rate Discrimination Sensitivity, and Speech Perception Performance in Postlingually Deafened Adult Cochlear Implant Users.

OBJECTIVE: This study assessed the relationships between the salience of amplitude modulation (AM) cues encoded at the auditory nerve (AN), perceptual sensitivity to changes in AM rate (i.e., AM rate discrimination threshold, AMRDT), and speech perception scores in postlingually deafened adult cochlear implant (CI) users. DESIGN: Study participants were 18 postlingually deafened adults with Cochlear Nucleus devices, including five bilaterally implanted patients. For each of 23 implanted ears, neural encoding of AM cues at 20 Hz at the AN was evaluated at seven electrode locations across the electrode array using electrophysiological measures of the electrically evoked compound action potential (eCAP). The salience of AM neural encoding was quantified by the Modulated Response Amplitude Ratio (MRAR). Psychophysical measures of AMRDT for 20 Hz modulation were evaluated in 16 ears using a three-alternative, forced-choice procedure, targeting 79.4% correct on the psychometric function. AMRDT was measured at up to five electrode locations for each test ear, including the electrode pair that showed the largest difference in the MRAR. Consonant-Nucleus-Consonant (CNC) word scores presented in quiet and in speech-shaped noise at a signal to noise ratio (SNR) of +10 dB were measured in all 23 implanted ears. Simulation tests were used to assess the variations in correlation results when using the MRAR and AMRDT measured at only one electrode location in each participant to correlate with CNC word scores. Linear Mixed Models (LMMs) were used to evaluate the relationship between MRARs/AMRDTs measured at individual electrode locations and CNC word scores. Spearman Rank correlation tests were used to evaluate the strength of association between CNC word scores measured in quiet and in noise with (1) the variances in MRARs and AMRDTs, and (2) the averaged MRAR or AMRDT across multiple electrodes tested for each participant. RESULTS: There was no association between the MRAR and AMRDT. Using the MRAR and AMRDT measured at only one, randomly selected electrode location to assess their associations with CNC word scores could lead to opposite conclusions. Both the results of LMMs and Spearman Rank correlation tests showed that CNC word scores measured in quiet or at 10 dB SNR were not significantly correlated with the MRAR or AMRDT. In addition, the results of Spearman Rank correlation tests showed that the variances in MRARs and AMRDTs were not significantly correlated with CNC word scores measured in quiet or in noise. CONCLUSIONS: The difference in AN sensitivity to AM cues is not the primary factor accounting for the variation in AMRDTs measured at different stimulation sites within individual CI users. The AN sensitivity to AM per se may not be a crucial factor for CNC word perception in quiet or at 10 dB SNR in postlingually deafened adult CI users. Using electrophysiological or psychophysical results measured at only one electrode location to correlate with speech perception scores in CI users can lead to inaccurate, if not wrong, conclusions.

Longitudinal Electrocochleography as an Objective Measure of Serial Behavioral Audiometry in Electro-Acoustic Stimulation Patients.

OBJECTIVE: Minimally traumatic surgical techniques and advances in cochlear implant (CI) electrode array designs have allowed acoustic hearing present in a CI candidate prior to surgery to be preserved postoperatively. As a result, these patients benefit from combined electric-acoustic stimulation (EAS) postoperatively. However, 30% to 40% of EAS CI users experience a partial loss of hearing up to 30 dB after surgery. This additional hearing loss is generally not severe enough to preclude use of acoustic amplification; however, it can still impact EAS benefits. The use of electrocochleography (ECoG) measures of peripheral hair cell and neural auditory function have shed insight into the pathophysiology of postimplant loss of residual acoustic hearing. The present study aims to assess the long-term stability of ECoG measures and to establish ECoG as an objective method of monitoring residual hearing over the course of EAS CI use. We hypothesize that repeated measures of ECoG should remain stable over time for EAS CI users with stable postoperative hearing preservation. We also hypothesize that changes in behavioral audiometry for EAS CI users with loss of residual hearing should also be reflected in changes in ECoG measures. DESIGN: A pool of 40 subjects implanted under hearing preservation protocol was included in the study. Subjects were seen at postoperative visits for behavioral audiometry and ECoG recordings. Test sessions occurred 0.5, 1, 3, 6, 12 months, and annually after 12 months postoperatively. Changes in pure-tone behavioral audiometric thresholds relative to baseline were used to classify subjects into two groups: one group with stable acoustic hearing and another group with loss of acoustic hearing. At each test session, ECoG amplitude growth functions for several low-frequency stimuli were obtained. The threshold, slope, and suprathreshold amplitude at a fixed stimulation level was obtained from each growth function at each time point. Longitudinal linear mixed effects models were used to study trends in ECoG thresholds, slopes, and amplitudes for subjects with stable hearing and subjects with hearing loss. RESULTS: Preoperative, behavioral audiometry indicated that subjects had an average low-frequency pure-tone average (125 to 500 Hz) of 40.88 ± 13.12 dB HL. Postoperatively, results showed that ECoG thresholds and amplitudes were stable in EAS CI users with preserved residual hearing. ECoG thresholds increased (worsened) while ECoG amplitudes decreased (worsened) for those with delayed hearing loss. The slope did not distinguish between EAS CI users with stable hearing and subjects with delayed loss of hearing. CONCLUSIONS: These results provide a new application of postoperative ECoG as an objective tool to monitor residual hearing and understand the pathophysiology of delayed hearing loss. While our measures were conducted with custom-designed in-house equipment, CI companies are also designing and implementing hardware and software adaptations to conduct ECoG recordings. Thus, postoperative ECoG recordings can potentially be integrated into clinical practice.

Characteristics of the Adaptation Recovery Function of the Auditory Nerve and Its Association With Advanced Age in Postlingually Deafened Adult Cochlear Implant Users.

OBJECTIVE: This study aimed to (1) characterize the amount and the speed of recovery from neural adaptation at the auditory nerve (AN) and (2) assess their associations with advanced age in postlingually deafened adult cochlear implant users. DESIGN: Study participants included 25 postlingually deafened adult, Cochlear Nucleus device users, ranging in age between 24.83 and 83.21 years at the time of testing. The stimulus was a 100-ms pulse train presented at four pulse rates: 500, 900, 1800, and 2400 pulses per second (pps). The pulse trains were presented at the maximum comfortable level measured for the 2400-pps pulse train. The electrically evoked compound action potential (eCAP) evoked by the last pulse of the pulse train (i.e., the probe pulse) was recorded. The remaining pulses of the pulse train served as the pulse-train masker. The time interval between the probe pulse and the last pulse of the pulse-train masker [i.e., masker-probe-interval (MPI)] systematically increased from 0.359 ms up to 256 ms. The adaptation recovery function (ARF) was obtained by plotting normalized eCAP amplitudes (re: the eCAP amplitude measured at the MPI of 256 ms) as a function of MPIs. The adaptation recovery ratio (ARR) was defined as the ratio between the eCAP amplitude measured at the MPI of 256 ms and that measured for the single-pulse stimulus presented at the same stimulation level. The time constants of the ARF were estimated using a mathematical model with an exponential function with up to three components. Generalized Linear Mixed effects Models were used to compare ARRs and time constants measured at different electrode locations and pulse rates, as well as to assess the effect of advanced age on these dependent variables. RESULTS: There were three ARF types observed in this study. The ARF type observed in the same study participant could be different at different electrode locations and/or pulse rates. Substantial variations in both the amount and the speed of neural adaptation recovery among study participants were observed. The ARR was significantly affected by pulse rate but was not affected by electrode location. The effect of electrode location on the time constants of the ARF was not statistically significant. Pulse rate had a statistically significant effect on τ 1, but not on τ 2 or τ 3 . There was no statistically significant effect of age on the ARR or the time constants of the ARF. CONCLUSIONS: Neural adaptation recovery processes at the AN demonstrate substantial variations among human cochlear implant users. The recovery pattern can be nonmonotonic with up to three phases. While the amount of neural adaptation recovery decreases as pulse rate increases, only the speed of the first phase of neural adaptation recovery is affected by pulse rate. Electrode location or advanced age has no robust effect on neural adaptation recovery processes at the level of the AN for a 100-ms pulse-train masker with pulse rates of 500 to 2400 pps. The lack of sufficient participants in this study who were 40 years of age or younger at the time of testing might have precluded a thorough assessment of the effect of advanced age.

Postlingually Deafened Adult Cochlear Implant Users With Prolonged Recovery From Neural Adaptation at the Level of the Auditory Nerve Tend to Have Poorer Speech Perception Performance.

OBJECTIVE: This study investigated the effects of two temporal response properties of the auditory nerve (i.e., neural adaptation and recovery from neural adaptation) on speech perception performance in postlingually deafened adult cochlear implant (CI) users. DESIGN: Study participants included 18 postlingually deafened adults who were Cochlear Nucleus device users with a full electrode array insertion in the test ear(s). Neural adaptation and adaptation recovery of the auditory nerve (AN) were evaluated using electrophysiological measures of the electrically evoked compound action potential (eCAP). The amount of neural adaptation was quantified by the adaptation index within three time windows: 0 to 8.89 (window 1), 44.44 to 50.00 (window 2), and 94.44 to 100.00 ms (window 3). The speed of neural adaptation was estimated using a two-parameter power law function. To evaluate adaptation recovery of the AN, eCAPs to the last pulse of the 100-ms pulse train were recorded at masker-probe-intervals ranging from 1.054 to 256 ms in logarithmic steps. The amount of adaptation recovery was quantified by the adaptation recovery ratio. The time-constant of adaptation recovery was estimated using an exponential function with up to three components. Speech perception performance was evaluated by measuring consonant-nucleus-consonant (CNC) word scores presented in quiet and in speech-shaped noise at a signal-to-noise ratio (SNR) of +10 dB. One-tailed Pearson Product Moment correlation tests were used (1) to assess the associations among parameters of neural adaptation and adaptation recovery and (2) to evaluate the strength of association between these parameters and CNC word scores measured in quiet and in noise. The contributions of different parameters quantifying neural adaptation and adaptation recovery on speech perception scores were evaluated using multivariable linear regression analyses. RESULTS: The Pearson Product Moment correlation coefficient demonstrated a moderate, negative correlation between the speed of adaptation recovery and CNC word scores measured in quiet and in noise. The speed of adaptation recovery accounted for 14.1% of variability in CNC word scores measured in quiet and 16.7% of variability in CNC word scores measured in noise. The correlation strengths between CNC word scores and the adaptation index, the adaptation recovery ratio and the speed of neural adaptation ranged from negligible to weak. CONCLUSIONS: The speed of adaptation recovery plays a more important role than other features of neural adaptation and adaptation recovery of the AN in speech perception in postlingually deafened adult CI users. Patients with prolonged adaptation recovery tend to show poorer speech perception performance.

The Effect of Advanced Age on the Electrode-Neuron Interface in Cochlear Implant Users.

OBJECTIVES: This study aimed to determine the effect of advanced age on how effectively a cochlear implant (CI) electrode stimulates the targeted cochlear nerve fibers (i.e., the electrode-neuron interface [ENI]) in postlingually deafened adult CI users. The study tested the hypothesis that the quality of the ENI declined with advanced age. It also tested the hypothesis that the effect of advanced age on the quality of the ENI would be greater in basal regions of the cochlea compared to apical regions. DESIGN: Study participants included 40 postlingually deafened adult CI users. The participants were separated into two age groups based on age at testing in accordance with age classification terms used by the World Health Organization and the Medical Literature Analysis and Retrieval System Online bibliographic database. The middle-aged group included 16 participants between the ages of 45 and 64 years and the elderly group included 24 participants older than 65 years. Results were included from one ear for each participant. All participants used Cochlear Nucleus CIs in their test ears. For each participant, electrophysiological measures of the electrically evoked compound action potential (eCAP) were used to measure refractory recovery functions and amplitude growth functions (AGFs) at three to seven electrode sites across the electrode array. The eCAP parameters used in this study included the refractory recovery time estimated based on the eCAP refractory recovery function, the eCAP threshold, the slope of the eCAP AGF, and the negative-peak (i.e., N1) latency. The electrode-specific ENI was evaluated using an optimized combination of the eCAP parameters that represented the responsiveness of cochlear nerve fibers to electrical stimulation delivered by individual electrodes along the electrode array. The quality of the electrode-specific ENI was quantified by the local ENI index, a value between 0 and 100 where 0 and 100 represented the lowest- and the highest-quality ENI across all participants and electrodes in the study dataset, respectively. RESULTS: There were no significant age group differences in refractory times, eCAP thresholds, N1 latencies or local ENI indices. Slopes of the eCAP AGF were significantly larger in the middle-aged group compared to the elderly group. There was a significant effect of electrode location on each eCAP parameter, except for N1 latency. In addition, the local ENI index was significantly larger (i.e., better ENI) in the apical region than in the basal and middle regions of the cochlea for both age groups. CONCLUSIONS: The model developed in this study can be used to estimate the quality of the ENI at individual electrode locations in CI users. The quality of the ENI is affected by the location of the electrode along the length of the cochlea. The method for estimating the quality of the ENI developed in this study holds promise for identifying electrodes with poor ENIs that could be deactivated from the clinical programming map. The ENI is not strongly affected by advanced age in middle-aged and elderly CI users.

Neural Adaptation of the Electrically Stimulated Auditory Nerve Is Not Affected by Advanced Age in Postlingually Deafened, Middle-aged, and Elderly Adult Cochlear Implant Users.

OBJECTIVE: This study aimed to investigate the associations between advanced age and the amount and the speed of neural adaptation of the electrically stimulated auditory nerve (AN) in postlingually deafened adult cochlear implant (CI) users. DESIGN: Study participants included 26 postlingually deafened adult CI users, ranging in age between 28.7 and 84.0 years (mean: 63.8 years, SD: 14.4 years) at the time of testing. All study participants used a Cochlear Nucleus device with a full electrode array insertion in the test ear. The stimulus was a 100-ms pulse train with a pulse rate of 500, 900, 1800, or 2400 pulses per second (pps) per channel. The stimulus was presented at the maximum comfortable level measured at 2400 pps with a presentation rate of 2 Hz. Neural adaptation of the AN was evaluated using electrophysiological measures of the electrically evoked compound action potential (eCAP). The amount of neural adaptation was quantified by the adaptation index (AI) within three time windows: around 0 to 8 ms (window 1), 44 to 50 ms (window 2), and 94 to 100 ms (window 3). The speed of neural adaptation was quantified using a two-parameter power law estimation. In 23 participants, four electrodes across the electrode array were tested. In three participants, three electrodes were tested. Results measured at different electrode locations were averaged for each participant at each pulse rate to get an overall representation of neural adaptation properties of the AN across the cochlea. Linear-mixed models (LMMs) were used (1) to evaluate the effects of age at testing and pulse rate on the speed of neural adaptation and (2) to assess the effects of age at testing, pulse rate, and duration of stimulation (i.e., time window) on the amount of neural adaptation in these participants. RESULTS: There was substantial variability in both the amount and the speed of neural adaptation of the AN among study participants. The amount and the speed of neural adaptation increased at higher pulse rates. In addition, larger amounts of adaptation were observed for longer durations of stimulation. There was no significant effect of age on the speed or the amount of neural adaptation. CONCLUSIONS: The amount and the speed of neural adaptation of the AN are affected by both the pulse rate and the duration of stimulation, with higher pulse rates and longer durations of stimulation leading to faster and greater neural adaptation. Advanced age does not affect neural adaptation of the AN in postlingually deafened, middle-aged and elderly adult CI users.

A Broadly Applicable Method for Characterizing the Slope of the Electrically Evoked Compound Action Potential Amplitude Growth Function.

OBJECTIVES: Amplitudes of electrically evoked compound action potentials (eCAPs) as a function of the stimulation level constitute the eCAP amplitude growth function (AGF). The slope of the eCAP AGF (i.e., rate of growth of eCAP amplitude as a function of stimulation level), recorded from subjects with cochlear implants (CIs), has been widely used as an indicator of survival of cochlear nerve fibers. However, substantial variation in the approach used to calculate the slope of the eCAP AGF makes it difficult to compare results across studies. In this study, we developed an improved slope-fitting method by addressing the limitations of previously used approaches and ensuring its application for the estimation of the maximum slopes of the eCAP AGFs recorded in both animal models and human listeners with various etiologies. DESIGN: The new eCAP AGF fitting method was designed based on sliding window linear regression. Slopes of the eCAP AGF estimated using this new fitting method were calculated and compared with those estimated using four other fitting methods reported in the literature. These four methods were nonlinear regression with a sigmoid function, linear regression, gradient calculation, and boxcar smoothing. The comparison was based on the fitting results of 72 eCAP AGFs recorded from 18 acutely implanted guinea pigs, 46 eCAP AGFs recorded from 23 chronically implanted guinea pigs, and 2094 eCAP AGFs recorded from 200 human CI users from 4 patient populations. The effect of the choice of input units of the eCAP AGF (linear versus logarithmic) on fitting results was also evaluated. RESULTS: The slope of the eCAP AGF was significantly influenced by the slope-fitting method and by the choice of input units. Overall, slopes estimated using all five fitting methods reflected known patterns of neural survival in human patient populations and were significantly correlated with speech perception scores. However, slopes estimated using the newly developed method showed the highest correlation with spiral ganglion neuron density among all five fitting methods for animal models. In addition, this new method could reliably and accurately estimate the slope for 4 human patient populations, while the performance of the other methods was highly influenced by the morphology of the eCAP AGF. CONCLUSIONS: The novel slope-fitting method presented in this study addressed the limitations of the other methods reported in the literature and successfully characterized the slope of the eCAP AGF for various animal models and CI patient populations. This method may be useful for researchers in conducting scientific studies and for clinicians in providing clinical care for CI users.

The Effect of Increasing Interphase Gap on N1 Latency of the Electrically Evoked Compound Action Potential and the Stimulation Level Offset in Human Cochlear Implant Users.

OBJECTIVE: This study reports two potential biomarkers of the physiological status of the cochlear nerve (CN) in cochlear implant users. DESIGN: This project represents a complementary analysis on a subset of electrophysiological data from our recently published study. This study compared changes in N1 latency and stimulation level (i.e., N1 latency offset and stimulation level offset) with increasing interphase gap of a biphasic pulse between children with cochlear nerve deficiency and children with normal-sized CNs. RESULTS: Children with cochlear nerve deficiency showed smaller N1 latency offsets and larger stimulation level offsets than children with normal-sized CNs at all electrode locations tested. CONCLUSIONS: The N1 latency and stimulation level offsets differ in two patient populations with different physiological statuses of the CN. These parameters may be useful for evaluating CN function in individual cochlear implant patients.

The Sensitivity of the Electrically Stimulated Auditory Nerve to Amplitude Modulation Cues Declines With Advanced Age.

OBJECTIVES: This study aimed to investigate effects of aging and duration of deafness on sensitivity of the auditory nerve (AN) to amplitude modulation (AM) cues delivered using trains of biphasic pulses in adult cochlear implant (CI) users. DESIGN: There were 21 postlingually deaf adult CI users who participated in this study. All study participants used a Cochlear Nucleus device with a full electrode array insertion in the test ear. The stimulus was a 200-ms pulse train with a pulse rate of 2000 pulses per second. This carrier pulse train was sinusodially AM at four modulation rates (20, 40, 100, 200 Hz). The peak amplitude of the modulated pulse train was the maximum comfortable level (i.e., C level) measured for the carrier pulse train. The electrically evoked compound action potential (eCAP) to each of the 20 pulses selected over the last two AM cycles were measured. In addition, eCAPs to single pulses were measured with the probe levels corresponding to the levels of 20 selected pulses from each AM pulse train. There were seven electrodes across the array evaluated in 16 subjects (i.e., electrodes 3 or 4, 6, 9, 12, 15, 18, and 21). For the remaining five subjects, 4 to 5 electrodes were tested due to impedance issues or time constraints. The modulated response amplitude ratio (MRAR) was calculated as the ratio of the difference in the maximum and the minimum eCAP amplitude measured for the AM pulse train to that measured for the single pulse, and served as the dependent variable. Age at time of testing and duration of deafness measured/defined using three criteria served as the independent variables. Linear Mixed Models were used to assess the effects of age at testing and duration of deafness on the MRAR. RESULTS: Age at testing had a strong, negative effect on the MRAR. For each subject, the duration of deafness varied substantially depending on how it was defined/measured, which demonstrates the difficulty of accurately measuring the duration of deafness in adult CI users. There was no clear or reliable trend showing a relationship between the MRAR measured at any AM rate and duration of deafness defined by any criteria. After controlling for the effect of age at testing, MRARs measured at 200 Hz and basal electrode locations (i.e., electrodes 3 and 6) were larger than those measured at any other AM rate and apical electrode locations (i.e., electrodes 18 and 21). CONCLUSIONS: The AN sensitivity to AM cues implemented in the pulse-train stimulation significantly declines with advanced age. Accurately measuring duration of deafness in adult CI users is challenging, which, at least partially, might have accounted for the inconclusive findings in the relationship between the duration of deafness and the AN sensitivity to AM cues in this study.

Prediction of the Functional Status of the Cochlear Nerve in Individual Cochlear Implant Users Using Machine Learning and Electrophysiological Measures.

OBJECTIVES: This study aimed to create an objective predictive model for assessing the functional status of the cochlear nerve (CN) in individual cochlear implant (CI) users. DESIGN: Study participants included 23 children with cochlear nerve deficiency (CND), 29 children with normal-sized CNs (NSCNs), and 20 adults with various etiologies of hearing loss. Eight participants were bilateral CI users and were tested in both ears. As a result, a total of 80 ears were tested in this study. All participants used Cochlear Nucleus CIs in their test ears. For each participant, the CN refractory recovery function and input/output (I/O) function were measured using electrophysiological measures of the electrically evoked compound action potential (eCAP) at three electrode sites across the electrode array. Refractory recovery time constants were estimated using statistical modeling with an exponential decay function. Slopes of I/O functions were estimated using linear regression. The eCAP parameters used as input variables in the predictive model were absolute refractory recovery time estimated based on the refractory recovery function, eCAP threshold, slope of the eCAP I/O function, and negative-peak (i.e., N1) latency. The output variable of the predictive model was CN index, an indicator for the functional status of the CN. Predictive models were created by performing linear regression, support vector machine regression, and logistic regression with eCAP parameters from children with CND and the children with NSCNs. One-way analysis of variance with post hoc analysis with Tukey's honest significant difference criterion was used to compare study variables among study groups. RESULTS: All three machine learning algorithms created two distinct distributions of CN indices for children with CND and children with NSCNs. Variations in CN index when calculated using different machine learning techniques were observed for adult CI users. Regardless of these variations, CN indices calculated using all three techniques in adult CI users were significantly correlated with Consonant-Nucleus-Consonant word and AzBio sentence scores measured in quiet. The five oldest CI users had smaller CN indices than the five youngest CI users in this study. CONCLUSIONS: The functional status of the CN for individual CI users was estimated by our newly developed analytical models. Model predictions of CN function for individual adult CI users were positively and significantly correlated with speech perception performance. The models presented in this study may be useful for understanding and/or predicting CI outcomes for individual patients.

The Effect of Pulse Polarity on Neural Response of the Electrically Stimulated Cochlear Nerve in Children With Cochlear Nerve Deficiency and Children With Normal-Sized Cochlear Nerves.

OBJECTIVE: This study aimed to (1) investigate the effect of pulse polarity on neural response of the electrically stimulated cochlear nerve in children with cochlear nerve deficiency (CND) and children with normal-sized cochlear nerves and (2) compare the size of the pulse polarity effect between these two subject groups. DESIGN: The experimental and control group included 31 children with CND and 31 children with normal-sized cochlear nerves, respectively. For each study participant, evoked compound action potential (eCAP) input/output (I/O) functions for anodic-leading and cathodic-leading biphasic stimuli were measured at three electrode locations across the electrode array. The dependent variables of interest included the eCAP amplitude measured at the maximum comfortable level of the anodic stimulus, the lowest level that could evoke an eCAP (i.e., the eCAP threshold), the slope of the eCAP I/O function estimated based on linear regression, the negative-peak (i.e., N1) latency of the eCAP, as well as the size of the pulse polarity effect on these eCAP measurements. Generalized linear mixed effect models were used to compare the eCAP amplitude, the eCAP threshold, the slope of the eCAP I/O function, and the N1 latency evoked by the anodic-leading stimulus with those measured for the cathodic-leading stimulus for children with CND and children with normal-sized cochlear nerves. Generalized linear mixed effect models were also used to compare the size of the pulse polarity effect on the eCAP between these two study groups. The one-tailed Spearman correlation test was used to assess the potential correlation between the pulse phase duration and the difference in N1 latency measured for different pulse polarities. RESULTS: Compared with children who had normal-sized cochlear nerves, children with CND had reduced eCAP amplitudes, elevated eCAP thresholds, flatter eCAP I/O functions, and prolonged N1 latencies. The anodic-leading stimulus led to higher eCAP amplitudes, lower eCAP thresholds, and shorter N1 latencies than the cathodic-leading stimulus in both study groups. Steeper eCAP I/O functions were recorded for the anodic-leading stimulus than those measured for the cathodic-leading stimulus in children with CND, but not in children with normal-sized cochlear nerves. Group differences in the size of the pulse polarity effect on the eCAP amplitude, the eCAP threshold, or the N1 latency were not statistically significant. CONCLUSIONS: Similar to the normal-sized cochlear nerve, the hypoplastic cochlear nerve is more sensitive to the anodic-leading than to the cathodic-leading stimulus. Results of this study do not provide sufficient evidence for proving the idea that the pulse polarity effect can provide an indication for local neural health.

The Effect of Interphase Gap on Neural Response of the Electrically Stimulated Cochlear Nerve in Children With Cochlear Nerve Deficiency and Children With Normal-Sized Cochlear Nerves.

OBJECTIVES: This study aimed to compare the effects of increasing the interphase gap (IPG) on the neural response of the electrically stimulated cochlear nerve (CN) between children with CN deficiency (CND) and children with normal-sized CNs. DESIGN: Study participants included 30 children with CND and 30 children with normal-sized CNs. All subjects were implanted with a Cochlear Nucleus device with the internal electrode array 24RE[CA] in the test ear. The stimulus was a charge-balanced, cathodic leading, biphasic pulse with a pulse-phase duration of 50 µsec. For each subject, the electrically evoked compound action potential (eCAP) input/output (I/O) function was measured for 6 IPGs (i.e., 7, 14, 21, 28, 35, and 42 µsec) at 3 electrode locations across the electrode array. For each subject and each testing electrode, the highest stimulation used to measure the eCAP I/O function was the maximum comfortable level measured with an IPG of 42 µsec. Dependent variables (DVs) were the maximum eCAP amplitude, the eCAP threshold, and the slope of the eCAP I/O function estimated using both linear and sigmoidal regression functions. For each DV, the size of the IPG effect was defined as the proportional change relative to the result measured for the 7 µsec IPG at the basal electrode location. Generalized linear mixed effect models with subject group, electrode location, and IPG duration as the fixed effects and subject as the random effect were used to compare these DVs and the size of the IPG effect on these DVs. RESULTS: Children with CND showed smaller maximum eCAP amplitudes, higher eCAP thresholds, and smaller slopes of eCAP I/O function estimated using either linear or sigmoidal regression function than children with normal-sized CNs. Increasing the IPG duration resulted in larger maximum eCAP amplitudes, lower eCAP thresholds and larger slopes of eCAP I/O function estimated using sigmoidal regression function at all three electrode locations in both study groups. Compared with children with normal-sized CNs, children with CND showed larger IPG effects on both the maximum eCAP amplitude and the slope of the eCAP I/O function estimated using either linear or sigmoidal regression function, and a smaller IPG effect on the eCAP threshold than those measured in children with normal-sized CNs. CONCLUSIONS: Increasing the IPG increases responsiveness of the electrically stimulated CN in both children with CND and children with normal-sized CNs. The maximum eCAP amplitude and the slope of the eCAP I/O function measured in human listeners with poorer CN survival are more sensitive to changes in the IPG. In contrast, the eCAP threshold in listeners with poorer CN survival is less sensitive to increases in the IPG. Further studies are warranted to identify the best parameters of eCAP results for predicting CN survival before this eCAP testing paradigm can be used as a clinical tool for evaluating neural health for individual cochlear implant patients.

Effect of Increasing Pulse Phase Duration on Neural Responsiveness of the Electrically Stimulated Cochlear Nerve.

OBJECTIVES: The aim of this study is to (1) investigate the effects of increasing the pulse phase duration (PPD) on the neural response of the electrically stimulated cochlear nerve (CN) in children with CN deficiency (CND) and (2) compare the results from the CND population to those measured in children with normal-sized CNs. DESIGN: Study participants included 30 children with CND and 30 children with normal-sized CNs. All participants used a Cochlear Nucleus device in the test ear. For each subject, electrically evoked compound action potential (eCAP) input/output (I/O) functions evoked by single biphasic pulses with different PPDs were recorded at three electrode locations across the electrode array. PPD durations tested in this study included 50, 62, 75, and 88 µsec/phase. For each electrode tested for each study participant, the amount of electrical charge corresponding to the maximum comfortable level measured for the 88 µsec PPD was used as the upper limit of stimulation. The eCAP amplitude measured at the highest electrical charge level, the eCAP threshold (i.e., the lowest level that evoked an eCAP), and the slope of the eCAP I/O function were measured. Generalized linear mixed effect models with study group, electrode location, and PPD as the fixed effects and subject as the random effect were used to compare these dependent variables measured at different electrode locations and PPDs between children with CND and children with normal-sized CNs. RESULTS: Children with CND had smaller eCAP amplitudes, higher eCAP thresholds, and smaller slopes of the eCAP I/O function than children with normal-sized CNs. Children with CND who had fewer electrodes with a measurable eCAP showed smaller eCAP amplitudes and flatter eCAP I/O functions than children with CND who had more electrodes with eCAPs. Increasing the PPD did not show a statistically significant effect on any of these three eCAP parameters in the two subject groups tested in this study. CONCLUSIONS: For the same amount of electrical charge, increasing the PPD from 50 to 88 µsec for a biphasic pulse with a 7 µsec interphase gap did not significantly affect CN responsiveness to electrical stimulation in human cochlear implant users. Further studies with different electrical pulse configurations are warranted to determine whether evaluating the eCAP sensitivity to changes in the PPD can be used as a testing paradigm to estimate neural survival of the CN for individual cochlear implant users.

On the effect of walking surface stiffness on inter-limb coordination in human walking: toward bilaterally informed robotic gait rehabilitation.

BACKGROUND: Robotic devices have been utilized in gait rehabilitation but have only produced moderate results when compared to conventional physiotherapy. Because bipedal walking requires neural coupling and dynamic interactions between the legs, a fundamental understanding of the sensorimotor mechanisms of inter-leg coordination during walking, which are not well understood but are systematically explored in this study, is needed to inform robotic interventions in gait therapy. METHODS: In this study we investigate mechanisms of inter-leg coordination by utilizing novel sensory perturbations created by real-time control of floor stiffness on a split-belt treadmill. We systematically alter the unilateral magnitude of the walking surface stiffness and the timing of these perturbations within the stance phase of the gait cycle, along with the level of body-weight support, while recording the kinematic and muscular response of the uperturbed leg. This provides new insight into the role of walking surface stiffness in inter-leg coordination during human walking. Both paired and unpaired unadjusted t-tests at the 95 % confidence level are used in the approriate scernario to determine statistical significance of the results. RESULTS: We present results of increased hip, knee, and ankle flexion, as well as increased tibialis anterior and soleus activation, in the unperturbed leg of healthy subjects that is repeatable and scalable with walking surface stiffness. The observed response was not impacted by the level of body-weight support provided, which suggests that walking surface stiffness is a unique stimulus in gait. In addition, we show that the activation of the tibialis anterior and soleus muscles is altered by the timing of the perturbations within the gait cycle. CONCLUSIONS: This paper characterizes the contralateral leg's response to ipsilateral manipulations of the walking surface and establishes the importance of walking surface stiffness in inter-leg coordination during human walking.

A new method for removing artifacts from recordings of the electrically evoked compound action potential: Single-pulse stimulation.

This report presents a new method for removing electrical artifact contamination from the electrically evoked compound action potential (eCAP) evoked by single cathodic-leading, biphasic-pulse stimulation. The development of the new method is motivated by results recorded in human cochlear implant (CI) users showing that the fundamental assumption of the classic forward masking artifact rejection technique is violated in up to 45% of cases tested at high stimulation levels when using default stimulation parameters. Subsequently, the new method developed based on the discovery that a hyperbola best characterizes the artifacts created during stimulation and recording is described. The eCAP waveforms obtained using the new method are compared to those recorded using the classic forward masking technique. The results show that eCAP waveforms obtained using both methods are comparable when the fundamental assumption of the classic forward masking technique is met. In contrast, eCAP amplitudes obtained using the two methods are significantly different when the fundamental assumption of the classic forward masking technique is violated, with greater differences in the eCAP amplitude for greater assumption violations. The new method also has excellent test-retest reliability (Intraclass correlation > 0.98). Overall, the new method is a viable alternative to the classic forward masking technique for obtaining artifact-free eCAPs evoked by single-pulse stimulation in CI users.

Peripheral neural synchrony in post-lingually deafened adult cochlear implant users.

Objective: This paper reports a noninvasive method for quantifying neural synchrony in the cochlear nerve (i.e., peripheral neural synchrony) in cochlear implant (CI) users, which allows for evaluating this physiological phenomenon in human CI users for the first time in the literature. In addition, this study assessed how peripheral neural synchrony was correlated with temporal resolution acuity and speech perception outcomes measured in quiet and in noise in post-lingually deafened adult CI users. It tested the hypothesis that peripheral neural synchrony was an important factor for temporal resolution acuity and speech perception outcomes in noise in post-lingually deafened adult CI users. Design: Study participants included 24 post-lingually deafened adult CI users with a Cochlear™ Nucleus® device. Three study participants were implanted bilaterally, and each ear was tested separately. For each of the 27 implanted ears tested in this study, 400 sweeps of the electrically evoked compound action potential (eCAP) were measured at four electrode locations across the electrode array. Peripheral neural synchrony was quantified at each electrode location using the phase locking value (PLV), which is a measure of trial-by-trial phase coherence among eCAP sweeps/trials. Temporal resolution acuity was evaluated by measuring the within-channel gap detection threshold (GDT) using a three-alternative, forced-choice procedure in a subgroup of 20 participants (23 implanted ears). For each ear tested in these participants, GDTs were measured at two electrode locations with a large difference in PLVs. For 26 implanted ears tested in 23 participants, speech perception performance was evaluated using Consonant-Nucleus-Consonant (CNC) word lists presented in quiet and in noise at signal-to-noise ratios (SNRs) of +10 and +5 dB. Linear Mixed effect Models were used to evaluate the effect of electrode location on the PLV and the effect of the PLV on GDT after controlling for the stimulation level effects. Pearson product-moment correlation tests were used to assess the correlations between PLVs, CNC word scores measured in different conditions, and the degree of noise effect on CNC word scores. Results: There was a significant effect of electrode location on the PLV after controlling for the effect of stimulation level. There was a significant effect of the PLV on GDT after controlling for the effects of stimulation level, where higher PLVs (greater synchrony) led to lower GDTs (better temporal resolution acuity). PLVs were not significantly correlated with CNC word scores measured in any listening condition or the effect of competing background noise presented at a SNR of +10 dB on CNC word scores. In contrast, there was a significant negative correlation between the PLV and the degree of noise effect on CNC word scores for a competing background noise presented at a SNR of +5 dB, where higher PLVs (greater synchrony) correlated with smaller noise effects on CNC word scores. Conclusions: This newly developed method can be used to assess peripheral neural synchrony in CI users, a physiological phenomenon that has not been systematically evaluated in electrical hearing. Poorer peripheral neural synchrony leads to lower temporal resolution acuity and is correlated with a larger detrimental effect of competing background noise presented at a SNR of 5 dB on speech perception performance in post-lingually deafened adult CI users.